1-substituted phenyl-1-(1h-imidazol-4-yl) alcohols, process for producing the same and use thereof

ABSTRACT

To provide a composition having a steroid C 17,20 -lyase inhibitory activity and useful as an agent for the prophylaxis or treatment of prostatism and tumors such as breast cancer. A compound represented by the formula:                    
     wherein R is a hydrogen atom or a protecting group, R 1  is a lower alkyl group or a cyclic hydrocarbon group, R 2  is an aromatic hydrocarbon group optionally having substituents or an aromatic heterocyclic group optionally having substituents, R 3  is a hydrocarbon group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, and n is an integer of 0 to 4, and a salt thereof have a steroid C 17,20 -lyase inhibitory activity, and are useful as an agent for the pophylaxis or treatment of prostatism and tumors such as beast cancer and the like.

This application is the National Phase filing of International PatentApplication No. PCT/JP00/07284, filed Oct. 19, 2000.

TECHNICAL FIELD

The present invention relates to a pharmaceutical agent, particularly, anovel 1-substituted phenyl-1-(1H-imidazol-4-yl)alcohol having a steroidC_(17,20)-lyase inhibitory action and a pharmaceutical compositioncontaining the same.

BACKGROUND ART

Sex hormones have various physiological activities such asdifferentiation and proliferation of cells and the like. On the otherhand, it has been found that androgen and estrogen act as anexacerbation factor in some diseases. It is known that steroidC_(17,20)-lyase is involved in the final stage in the biosynthesis ofandrogen in vivo. That is, steroid C_(17,20)-lyase converts, as asubstrate, 17-hydroxypregnenolone and 17-hydroxyprogesterone derivedfrom cholesterol to dehydroepiandrosterone and androstenedione,respectively. Therefore, a medicine having a steroid C_(17,20)-lyaseinhibitory activity suppresses formation of androgen, as well asestrogen produced from androgen as a substrate, and is useful as anagent for the prophylaxis or treatment of diseases whose exacerbationfactor is androgen or estrogen. As the disease for which androgen orestrogen is an exacerbation factor, there are mentioned, for example,prostate cancer, prostatic hypertrophy, virilism, hirsutism, malepattern alopecia, precocious puberty, breast cancer, uterine cancer,ovarian cancer, mastopathy, uterus myoma, endometriosis, adenomyosis ofuterus, polycystic ovary syndrome, and the like.

Steroid type compounds and non-steroid type compounds are already knownas steroid C₁₇₋₂₀-lyase inhibitors. The steroid type compounds aredisclosed in, for example, WO 92/15404, WO 93/20097, EP-A 288053, EP-A413270 and the like. As non-steroid type compounds, for example,(1H-imidazol-1-yl)methyl-substituted benzimidazole derivatives are shownin Japanese Published Unexamined Patent Application No. 85975/1989,carbazole derivatives are shown in WO94/27989 and WO96/14090, azolederivatives are shown in WO95/09157, 1H-benzimidazole derivatives areshown in U.S. Pat. No. 5,491,161, dihydronaphthalene derivatives areshown in WO99/18075, and (1H-imidazol-1-yl)methylbiphenyl derivativesare shown in Bioorganic Medicinal Chemistry, vol. 7, pp 1913-1924(1999).

Heretofore, steroid C_(17,20)-lyase inhibitors usable for medicalpurposes have not been obtained, and early development of steroidC_(17,20)-lyase inhibitors highly useful as medicine is awaited.

DISCLOSURE OF INVENTION

The present inventors have conducted intensive studies in an attempt tofind a superior steroid C_(17,20)-lyase inhibitor and first synthesizeda novel compound characterized by a chemical structure, wherein amethylene group that connects a benzene ring represented by the formula(I) and an imidazole ring is substituted by lower alkyl or cyclichydrocarbon group and hydroxyl group, and a salt thereof, and found thatthe obtained compound (I) and a salt thereof have, based on the specificchemical structure, unexpectedly superior pharmaceutical use,particularly a superior steroid C_(17,20)-lyase inhibitory activity, lowtoxicity and superior properties as a pharmaceutical product, and basedon these findings, completed the present invention.

Accordingly, the present invention relates to

(1) a compound represented by the formula:

 wherein

R is a hydrogen atom or a protecting group,

R¹ is a lower alkyl group or a cyclic hydrocarbon group,

R² is an aromatic hydrocarbon group optionally having substituents or anaromatic heterocyclic group optionally having substituents,

R³ is a hydrocarbon group optionally having substituents, a hydroxylgroup optionally having substituents, a thiol group optionally havingsubstituents, an amino group optionally having substituents, an acylgroup or a halogen atom, and

n is an integer of 0 to 4,

or a salt thereof;

(2) the compound of the above-mentioned (1), wherein R is 1) a hydrogenatom, 2) a formyl, 3) a C₁₋₆ alkylcarbonyl optionally substituted by 1to 3 groups selected from Group 1, 4) a phenylcarbonyl optionallysubstituted by 1 to 3 groups selected from Group 1, 5) a C₁₋₆alkyl-oxycarbonyl optionally substituted by 1 to 3 groups selected fromGroup 1, 6) a phenyloxycarbonyl optionally substituted by 1 to 3 groupsselected from Group 1, 7) a C₇₋₁₀ aralkyloxy-carbonyl optionallysubstituted by 1 to 3 groups selected from Group 1, 8) a trityloptionally substituted by 1 to 3 groups selected from Group 1, 9) aphthaloyl optionally substituted by 1 to 3 groups selected from Group 1or 10) a N,N-dimethylaminomethylene optionally substituted by 1 to 3groups selected from Group 1,

R¹ is a C₁₋₆ alkyl or a C₃₋₆ cycloalkyl,

R² is a C₆₋₁₀ aryl group optionally substituted by 1 to 4 groupsselected from Group 2 or an aromatic heterocyclic group selected fromGroup 3, which is optionally substituted by 1 to 4 groups selected fromGroup 2, and

R³ is 1) a C₁₋₄ alkyl, 2) a C₁₋₄ alkyl having C₂₋₄ alkanoyl, carboxyl orC₁₋₄ alkoxy-carbonyl as a substituent, 3) a hydroxyl group, 4) a C₁₋₄lower alkoxy, 5) a C₁₋₄ alkanoyloxy, 6) a carbamoyloxy, 7) acarbamoyloxy substituted by 1 or 2 C₁₋₄ alkyl groups, 8) a thiol group,9) a C₁₋₄ alkylthio group, 10) a C₁₋₄ alkanoylthio, 11) an amino group,12) a C₁₋₄ alkylamino group, 13) a di-C₁₋₄ alkylamino, 14) a C₁₋₄alkanoylamino, 15) a formyl, 16) a C₂₋₆ alkanoyl, 17) a C₁₋₄alkylsulfonyl, 18) a carbamoyl group, 19) a mono- or di-C₁₋₁₀alkylcarbamoyl group, 20) a mono- or di-C₆₋₁₄ arylcarbamoyl, 21) a mono-or di-C₇₋₁₆ aralkylcarbamoyl group, 22) a sulfamoyl, 23) a mono- ordi-C₁₋₁₀ alkylsulfamoyl group, 24) a mono- or di-C₆₋₁₄ arylsulfamoylgroup, 25) a mono- or di-C₇₋₁₆ aralkylsulfamoyl group or 26) a halogenatom,

and wherein, in the above,

Group 1 includes

a halogen atom, a formyl group, a C₁₋₆ alkyl-carbonyl group and a nitrogroup,

Group 2 includes

1) a C₁₋₆ alkyl group, 2) a C₁₋₄ alkyl group substituted by 1 to 5halogen atoms, 3) a C₁₋₄ alkyl group substituted by 1 or 2 C₁₋₄ alkoxy,4) a hydroxyl group, 5) a C₁₋₄ alkoxy group, 6) a C₁₋₄ alkanoyloxygroup, 7) a carbamoyloxy group, 8) a carbamoyloxy group substituted byC₁₋₄ alkyl group, 9) an amino group, 10) a mono- or di-C₁₋₄ alkylaminogroup, 11) a C₁₋₄ alkanoylamino group, 12) a formyl group, 13) a C₂₋₆alkanoyl group, 14) a C₁₋₄ alkylsulfonyl group, 15) a carbamoyl group,16) a mono- or di-C₁₋₁₀ alkylcarbamoyl group, 17) a C₃₋₆cycloalkylcarbamoyl group, 18) a mono- or di-C₆₋₁₄ arylcarbamoyl group,19) a mono- or di-C₇₋₁₆ aralkylcarbamoyl group, 20) a sulfamoyl group,21) a mono- or di-C₁₋₁₀ alkylsulfamoyl group, 22) a mono- or di-C₆₋₁₄arylsulfamoyl group, 23) a mono- or di-C₇₋₁₆ aralkylsulfamoyl group, 24)a halogen atom, 25) a cyano group and 26) an oxo group,

Group 3 includes

a 2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridylgroup, a 4-pyridyl group, a 2-furyl group, a 3-furyl group, a 2-quinolylgroup, a 4-quinolyl group, a 8-quinolyl group, a 3-isoquinolyl group, a4-isoquinolyl group, a pyrazinyl group, a 2-pyrimidinyl group, a3-pyrrolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a1-pyrazolyl group, a 2-thiazolyl group, a 4-thiazolyl group, a5-thiazolyl group, a 3-isothiazolyl group, a 4-isothiazolyl group, a2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, a 3-isoxazolylgroup, a 3-pyridazinyl group, a 1-indolyl group, a 1-isoindolyl group, a2-isoindolyl group, a 1-tetrazolyl group, a 2-tetrazolyl group and a5-tetrazolyl group;

(3) the compound of the above-mentioned (1), wherein

R is a hydrogen atom,

R¹ is a C₁₋₆ alkyl group or a C₃₋₆ cycloalkyl group,

R² is a phenyl group, a pyridyl group, a thienyl group, a furyl group oran isoindolinyl group, each optionally substituted by 1 to 4 groupsselected from Group 4,

n is 0 or 1, and

R³ is a C₁₋₄ lower alkoxy group, a C₁₋₄ alkanoyloxy group or a C₁₋₄alkanoylamino group,

 and wherein, in the above,

Group 4 includes

1) a C₁₋₆ alkyl group, 2) a C₁₋₄ alkyl group substituted by 1 to 5halogen atoms, 3) a C₁₋₄ alkyl group substituted by 1 or 2 C₁₋₄ alkoxy,4) a C₁₋₄ alkoxy group, 5) a C₁₋₄ alkanoylamino group, 6) a C₂₋₆alkanoyl group, 7) a mono- or di-C₁₋₁₀ alkylcarbamoyl group, 8) a C₃₋₆cycloalkylcarbamoyl group, 9) a mono- or di-C₁₋₁₀ alkylsulfamoyl group,10) a halogen atom, 11) a cyano group and 12) an oxo group;

(4) the compound of the above-mentioned (3), wherein R² is a phenylgroup, a pyridyl group, a thienyl group, a furyl group or anisoindolinyl group, each optionally substituted by 1 or 2 groupsselected from Group 5,

and wherein, in the above,

Group 5 includes

1) a C₁₋₄ alkanoylamino group, 2) a C₂₋₆ alkanoyl group, 3) a mono-C₁₋₁₀alkylcarbamoyl group, 4) a mono-C₁₋₁₀ alkylsulfamoyl group, 5) a halogenatom and 6) an oxo group;

(5) the compound of the above-mentioned (1), wherein

R is a hydrogen atom,

R¹ is a C₁₋₆ alkyl group,

R² is 1) a phenyl group substituted by halogen or acetylamino or 2) apyridyl group substituted by halogen or acetylamino, and

n is 0;

(6) the compound of the above-mentioned (1), which is1-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,(−)-N-(6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridyl)acetamide,(−)-N-{4′-[1-hydroxy-1-1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide,4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamideorN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl]acetamide,or a salt thereof;

(7) a prodrug of a compound represented by the formula:

 wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, or a salt thereof;

(8) a pharmaceutical composition containing a compound represented bythe formula:

 wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, a salt thereof or a prodrug thereof;

(9) the composition of the above-mentioned (8), which is a steroidC_(17,20)-lyase inhibitor;

(10) the composition of the above-mentioned (9), which is an antitumoragent;

(11) the antitumor composition of the above-mentioned (9), which is anagent for the prophylaxis or treatment of breast cancer or prostatecancer;

(12) an androgen reducer containing a compound represented by theformula:

 wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, or a salt thereof or a prodrug thereof, and an LHRHmodulator in combination;

(13) a production method of a compound represented by the formula:

 wherein

R is a hydrogen atom or a protecting group,

R¹ is a lower alkyl group or a cyclic hydrocarbon group,

R² is an aromatic hydrocarbon group optionally having substituents or anaromatic heterocyclic group optionally having substituents,

R³ is a hydrocarbon group optionally having substituents, a hydroxylgroup optionally having substituents, a thiol group optionally havingsubstituents, an amino group optionally having substituents, an acylgroup or a halogen atom, and

n is an integer of 0 to 4, or a salt thereof,

 which method comprises reacting a compound represented by the formula:

wherein each symbol is as defined above, with a reaction product of acompound represented by the formula:

wherein X is a leaving group and R is as defined above, and a Grignardreagent or alkyllithium;

(14) a method for inhibiting steroid C_(17,20)-lyase, which comprisesadministering, to a mammal, an effective amount of a compoundrepresented by the formula:

 wherein

R is a hydrogen atom or a protecting group,

R¹ is a lower alkyl group or a cyclic hydrocarbon group,

R² is an aromatic hydrocarbon group optionally having substituents or anaromatic heterocyclic group optionally having substituents,

R³ is a hydrocarbon group optionally having substituents, a hydroxylgroup optionally having substituents, a thiol group optionally havingsubstituents, an amino group optionally having substituents, an acylgroup or a halogen atom, and

n is an integer of 0 to 4,

or a salt or a prodrug thereof;

(15) use of a compound represented by the formula:

 wherein

R is a hydrogen atom or a protecting group,

R¹ is a lower alkyl group or a cyclic hydrocarbon group,

R² is an aromatic hydrocarbon group optionally having substituents or anaromatic heterocyclic group optionally having substituents,

R³ is a hydrocarbon group optionally having substituents, a hydroxylgroup optionally having substituents, a thiol group optionally havingsubstituents, an amino group optionally having substituents, an acylgroup or a halogen atom,

n is an integer of 0 to 4,

or a salt thereof or a prodrug thereof for the production of a steroidC_(17,20)-lyase inhibitor; and the like.

In the above formulas, the lower alkyl group represented by R¹ is astraight chain or branched alkyl having 1 to 6 carbon atoms. Examplesthereof include C₁₋₆ alkyl group such as methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, tert-pentyl, n-hexyl, isohexyl and the like. Examples of thecyclic hydrocarbon group represented by R¹ include C₃₋₆ cycloalkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like,and the like. As R¹, C₁₋₄ alkyl group (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tertbutyl etc.) and the like arepreferable.

Examples of the “aromatic hydrocarbon group” in “aromatic hydrocarbongroup optionally having substituents”, which is represented by R²,include a monocyclic aromatic hydrocarbon group, a condensed polycyclicaromatic hydrocarbon group and the like, each of which consisting of 6to 18 carbon atoms. Specific examples thereof include a C₆₋₁₄ aryl groupsuch as phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl and thelike, with preference given to C₆₋₁₀ aryl group (e.g., phenyl etc.) andthe like. Examples of the “aromatic heterocyclic group” in “aromaticheterocyclic group optionally having substituents”, which is representedby R², include 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-furyl, 3-furyl, 2-quinolyl, 4-quinolyl, 8-quinolyl, 3-isoquinolyl,4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl,2-imidazolyl, 1-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,3-isothiazolyl, 4-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 3-pyridazinyl, 1-indolyl, 1-isoindolyl, 2-isoindolyl,1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl and the like.

The “substituent” in the “aromatic hydrocarbon group optionally havingsubstituents” and “aromatic heterocyclic group optionally havingsubstituents”, which is represented by R², may be present in the numberof 1 to 4 at substitutable positions on the ring. Examples of thesubstituent include lower(C₁₋₆)alkyl group (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl and thelike), lower alkyl group substituted by 1 to 5 halogen atoms (e.g.,fluorine, chlorine and the like), which is exemplified by those having 1to 4 carbon atoms such as chloromethyl, bromoethyl, fluoromethyl,trichloromethyl, 1-chloroethyl, 2-chloroethyl, 1,1-dichloroethyl,1,2-dibromoethyl, 1,1,2-trichloropropyl and the like, C₁₋₄ alkyl groupsubstituted by 1 or 2 C₁₋₄ alkoxy (e.g., methoxymethyl, ethoxymethyl,1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl,dimethoxymethyl and the like), hydroxyl group optionally havingsubstituents [e.g., hydroxyl group, lower alkoxy (e.g., C₁₋₄ alkoxygroup such as methoxy, ethoxy, propoxy and the like), lower alkanoyloxy(e.g., C₁₋₄ alkanoyloxy such as acetyloxy, propionyloxy and the like),carbamoyloxy optionally having substituents (e.g., unsubstitutedcarbamoyloxy and carbamoyloxy substituted by 1 or 2 C₁₋₄ alkyl groups,such as methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy, methylethylcarbamoyloxy and the like) and thelike], amino group optionally having substituents [e.g., amino, loweralkylamino (e.g., C₁₋₄ alkylamino group such as methylamino, ethylamino,propylamino and the like), di-lower alkylamino (e.g., di-C₁₋₄ alkylaminosuch as dimethylamino, diethylamino and the like), C₁₋₄ alkanoylamino(e.g., acetamide, propionamide and the like) and the like], acyl group[e.g., carbamoyl group optionally having substituents (e.g., mono- ordi-C₁₋₁₀ alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl etc., mono- or di-C₆₋₁₄arylcarbamoyl such as phenylcarbamoyl, diphenylcarbamoyl etc., mono- ordi-C₇₋₁₆ aralkylcarbamoyl group such as benzylcarbamoyl,dibenzylcarbamoyl etc., and the like), alkanoyl group (e.g., C₁₋₆alkanoyl such as formyl, acetyl, propionyl and the like), alkylsulfonylgroup (e.g., C₁₋₄ alkylsulfonyl such as methylsulfonyl, ethylsulfonyland the like), carbamoyl group optionally having substituents (e.g.,mono- or di-C₁₋₁₀ alkylcarbamoyl group such as methylcarbamoyl,ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl etc., C₃₋₆cycloalkylcarbamoyl such as cyclopropylcarbamoyl, cyclopentylcarbamoyl,cyclohexylcarbamoyl etc., mono- or di-C₆₋₁₄ arylcarbamoyl such asphenylcarbamoyl, diphenylcarbamoyl etc., mono- or di-C₇₋₁₆aralkylcarbamoyl group such as benzylcarbamoyl, dibenzylcarbamoyl etc.,and the like), sulfamoyl optionally having substituents (e.g., mono- ordi-C₁₋₁₀ alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl,dimethylsulfamoyl, diethylsulfamoyl etc., mono- or di-C₆₋₁₄arylsulfamoyl group such as phenylsulfamoyl, diphenylsulfamoyl etc.,mono- or di-C₇₋₁₆ aralkylsulfamoyl group such as benzylsulfamoyl,dibenzylsulfamoyl etc., and the like) and the like], halogen atom(fluorine, chlorine, bromine, iodine) and the like.

Examples of the hydrocarbon group optionally having substituents, whichis represented by R³, include unsubstituted C₁₋₄ alkyl such as methyl,ethyl, propyl etc., these alkyl groups having substituents such asalkanoyl (e.g., acetyl, propionyl etc.), carboxyl, C₁₋₄ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl etc.) and thelike, and the like.

Examples of the hydroxyl group optionally having substituents, which isrepresented by R³, include unsubstituted hydroxyl group, lower alkoxy(e.g., C₁₋₄ alkoxy group such as methoxy, ethoxy, propoxy etc.), loweralkanoyloxy (e.g., C₁₋₄ alkanoyloxy such as acetyloxy, propionyloxyetc.), carbamoyloxy optionally having substituents (e.g., unsubstitutedcarbamoyloxy, carbamoyloxy substituted by 1 or 2 C₁₋₄ alkyl groups suchas methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy, methylethylcarbamoyloxy etc.) and the like.

Examples of the thiol group optionally having substituents, which isrepresented by R³, include unsubstituted thiol group, lower alkylthio(e.g., C₁₋₄ alkylthio group such as methylthio, ethylthio, propylthioetc.), lower alkanoylthio (e.g., C₁₋₄ alkanoylthio such as acetylthio,propionylthio etc.) and the like.

Examples of the amino group optionally having substituents, which isrepresented by R³, include unsubstituted amino group, lower alkylamino(e.g., C₁₋₄ alkylamino group such as methylamino, ethylamino,propylamino etc.), di-lower alkylamino (e.g., di-C₁₋₄ alkylamino such asdimethylamino, diethylamino etc.), C₁₋₄ alkanoylamino (e.g., acetamide,propionamide etc.), and the like.

Examples of the acyl group represented by R³ include alkanoyl group(e.g., C₁₋₆ alkanoyl such as formyl, acetyl, propionyl etc.),alkylsulfonyl group (e.g., C₁₋₄ alkylsulfonyl such as methylsulfonyl,ethylsulfonyl etc.), carbamoyl group optionally having substituents(e.g., mono- or di-C₁₋₁₀ alkylcarbamoyl group such as methylcarbamoyl,ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl etc., mono- ordi-C₆₋₁₄ arylcarbamoyl such as phenylcarbamoyl, diphenylcarbamoyl etc.,mono- or di-C₇₋₁₆ aralkylcarbamoyl group such as benzylcarbamoyl,dibenzylcarbamoyl etc., and the like), sulfamoyl optionally havingsubstituents (e.g., mono- or di-C₁₋₁₀ alkylsulfamoyl group such asmethylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyletc., mono- or di-C₆₋₁₄ arylsulfamoyl group such as phenylsulfamoyl,diphenylsulfamoyl etc., mono- or di-C₇₋₁₆ aralkylsulfamoyl group such asbenzylsulfamoyl, dibenzylsulfamoyl etc., and the like), and the like.

Examples of the halogen atom represented by R³ include fluorine,chlorine, bromine and iodine.

Examples of the protecting group represented by R include C₁₋₆alkylcarbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl, C₁₋₆alkyl-oxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl etc.),phenyloxycarbonyl, C₇₋₁₀ aralkyloxycarbonyl (e.g., phenyl-C₁₋₄alkyloxy-carbonyl such as benzyloxycarbonyl etc. and the like), trityl,phthaloyl and N,N-dimethylaminomethylene, each of which may besubstituted, and formyl. Examples of the substituent include halogenatom (e.g., fluorine, chlorine, bromine, iodine etc.), formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, valeryl etc.), nitro group andthe like, wherein the number of substituent is about 1 to 3.

Examples of the leaving group represented by X include halogen atom(chlorine atom, bromine atom, iodine atom etc.), alkyl oraryl-sulfonyloxy group (methanesulfonyloxy, ethanesulfonyloxy,benzenesulfonyloxy, p-toluenesulfonyloxy etc.), and the like.

The compound represented by the formula (I) of the present invention mayform a salt. Examples of the salt include acid addition salt such asinorganic acid salt (e.g., hydrochloride, sulfate, hydrobromide,phosphate etc.), organic acid salt (e.g., acetate, trifluoroacetate,succinate, maleate, fumarate, propionate, citrate, tartrate, lactate,oxalate, methanesulfonate, p-toluenesulfonate etc.) and the like.

The compound represented by the formula (I) and a salt thereof may be ahydrate, and in the following, compound (I) also encompasses salts andhydrates.

The prodrug of Compound (I) means a compound which is converted tocompound (I) having a steroid C_(17,20)-lyase inhibitory activity by invivo reactions of enzymes, gastric acid and the like.

Examples of the prodrug of compound (I) include a compound obtained bysubstituting nitrogen atom of imidazole of compound (I) with acyl oralkyl (e.g., compound wherein the nitrogen atom has been substitutedwith dimethylaminosulfonyl, acetoxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylmethyl,pivaloyloxymethyl, benzyloxymethyl etc.); a compound obtained bysubstituting hydroxy group of compound (I) with acyl, alkyl, phosphate,sulfate, borate, (e.g., compound (I) wherein the hydroxy group has beensubstituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl,fumaryl, alanyl, dimethylaminomethylcarbonyl etc.); and the like. Thesecompounds can be produced by a method known per se.

The prodrug of compound (I) may be as it is or a pharmaceuticallyacceptable salt. When the prodrug of compound (I) has an acidic groupsuch as a carboxyl group, examples of the salt include a salt with aninorganic base (e.g., alkali metal such as sodium, potassium etc.;alkaline earth metal such as calcium, magnesium etc.; transition metalsuch as zinc, iron, copper etc., and the like); an organic base (e.g.,organic amines such as trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like, basicamino acids such as arginine, lysin, ornithine and the like) and thelike.

When the prodrug of compound (I) has a basic group such as an aminogroup and the like, examples of the salt include salt with inorganicacid or organic acid (e.g., hydrochloric acid, nitric acid, sulfuricacid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid,acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidetc.); acidic amino acids such as aspartic acid, glutamic acid etc.; andthe like.

In addition, the prodrug of compound (I) may be a hydrate or anon-hydrate.

Compound (I) may have one or more asymmetric carbons in the molecule.The compound of the present invention also encompasses R-configurationand S-configuration at the asymmetric carbons.

Throughout the specification, of the compounds shown by the formulas(I), (I′), (II), (III), (III′), (IV), (IV′), (V), (VI), (VIII), (VIII′)and (IX), a compound having a basic group or an acidic group can form asalt with an acid or a salt with a base, respectively. Examples of thesalt with an acid and the salt with a base include those similar to thesalts of the compound (I) mentioned above. Hereinafter the compoundsrepresented by each formula and its salt are referred to as compound(symbol of formula). For example, a compound of formula (II) and a saltthereof are simply referred to as compound (II).

The compound (I) can be produced, for example, by the following methodand the like.

The starting compound and synthetic intermediates can be used in a freeform or as a salt thereof like compound (I), and they may be used for areaction as a reaction mixture or after isolation by a known method.

wherein M is a metal or a salt thereof, and the other symbols are asdefined above.

Examples of the metal shown by M include lithium, magnesium and thelike. Examples of a salt thereof include metal halide such as magnesiumchloride, magnesium bromide, and the like.

[Steps A and B]

The compound (I) can be obtained by reacting compound (II) with anorganic metal compound (III′). That is, compound (III) is reacted withalkyllithium, alkylmagnesium halide and the like to give an organicmetal compound (III′), which is then reacted with compound (II) to givecompound (I).

Examples of the alkyllithium used in the reaction include a C₁₋₄alkyllithium such as n-butyllithium, s-butyllithium,tert-butyllithiumetc and the like. Alkyllithium is used in an amount of1 to 3 moles, preferably 1 to 1.5 mole, per mole of the startingcompound (III) or (IV). When alkyllithium is reacted, the reactiontemperature is in the range of from −100° C. to 0° C., preferably −80°C. to −20° C. Examples of alkylmagnesium halide include ethylmagnesiumbromide, methylmagnesium chloride and the like. The amount ofalkylmagnesium halide to be used is 1 to 10 moles, preferably 1 to 4moles, per mole of the starting compound (III). When compound (III) isreacted with alkyl magnesium halide, the reaction temperature is in therange of from −40° C. to 20° C., preferably −20° C. to 0° C. Thereaction time is about 5 minutes to 20 hours. The reaction is usuallycarried out in an organic solvent that does not affect the reaction.Examples of the organic solvent which does not affect the reactioninclude ether such as diethyl ether, dioxane, tetrahydrofuran (THF) andthe like, saturated hydrocarbon such as hexane, pentane and the like,halogenated hydrocarbon such as dichloromethane, chloroform and thelike, aromatic hydrocarbon such as benzene, toluene and the like, andthe like. These solvents may be used alone or in combination of two ormore kinds thereof in an appropriate mixing ratio. The Compound (II) isused in 0.1 to 10 equivalents, preferably 0.2 to 2 equivalents, relativeto Compound (III).

[Steps C and D]

The Compound (I) can be also obtained by reacting compound (IV) with ametal, such as an alkyllithium, magnesium and the like, to give anorganic metal compound (IV′), which is then reacted with compound (V).Examples of alkyllithium used in the reaction include a C₁₋₄alkyllithium such as nbutyllithium, s-butyllithium, t-butyllithium andthe like. Alkyllithium is used in an amount of 1 to 3 moles, preferably1 to 1.5 moles, per mole of starting compound (III) or (IV). Whenalkyllithium is reacted, the reaction temperature is in the range offrom −100° C. to 0° C., preferably −80° C. to −20° C. When compound (IV)is reacted with magnesium metal, the amount of magnesium metal used isin the range of from 1 to 3 moles, preferably 1 to 1.5 moles, per moleof compound (IV), and the reaction temperature is in the range of from−20° C. to 100° C., preferably 10° C. to 50° C. The reaction time isabout 5 minutes to 20 hours. The reaction is usually carried out in anorganic solvent that does. not affect to the reaction. Examples of theorganic solvent which does not affect to the reaction include ether suchas diethyl ether, dioxane, tetrahydrofuran (THF) and the like, saturatedhydrocarbon such as hexane, pentane and the like, halogenatedhydrocarbon such as dichloromethane, chloroform and the like, aromatichydrocarbon such as benzene, toluene and the like, and the like. Thesesolvents may be used alone or in combination of two or more kindsthereof in an appropriate mixing ratio. The compound (V) is used in 0.1to 10 equivalents, preferably 0.2 to 2 equivalents, relative to compound(IV).

[Step E]

The Compound (I) can be also obtained by reacting compound (VI) with anorganic metal reagent (VII).

The amount of compound (VII) to be used is in the range of from 1 to 10moles, preferably 1 to 5 moles, per mole of compound (VI), and thereaction temperature is in the range of from −80° C. to 60° C.,preferably −80° C. to 50° C. The reaction time is about 5 minutes to 20hours. The reaction is usually carried out in an organic solvent thatdoes not affect the reaction. Examples of the solvent which does notaffect the reaction include ether such as diethyl ether, dioxane,tetrahydrofuran (THF) and the like, saturated hydrocarbon such ashexane, pentane and the like, halogenated hydrocarbon such asdichloromethane, chloroform and the like, aromatic hydrocarbon such asbenzene, toluene and the like, and the like. These solvents may be usedalone or in combination of two or more kinds thereof in a suitablemixing ratio.

[Step F]

When R of compound (I) is a protecting group, the protecting group iseliminated by a method known per se or a method similar thereto to givecompound (I′). For example, when R is a trityl group, the trityl groupcan be removed by a treatment under acidic conditions or hydrogenolysis.Examples of the acid include organic acid such as formic acid, aceticacid and the like, inorganic acid such as hydrochloric acid and thelike, and the like. The reaction can be carried out in a solvent inertto the reaction, such as alcohol, ether (e.g., THF etc.) and the like.The reaction temperature is usually 0° C. to 100° C.

wherein Y is a leaving group (halogen atom, alkyl, arylsulfonyloxy groupetc.) or a substituent capable of converting to a leaving group (e.g.,protected hydroxyl group), Z is a leaving group such as trialkyltin,boric acid and the like, and other symbols are as defined above.

[Steps G and H]

In steps G and H, compound (VIII) is reacted with a metal, such asalkyllithium, magnesium etc., to give an organic metal compound (VIII′),which is reacted with compound (V) to give compound (IX). The reactionconditions are as above-mentioned with regard to Steps A and B. When Yof compound (VIII) is a protected hydroxyl group (e.g., trialkylsilyloxygroup) that can be converted to a leaving group, the compound isconverted to compound (IX), after which Y is preferably converted to aleaving group (e.g., trifluoromethanesulfonyloxy group). This conversioncan be carried out according to a conventional method.

[Step I]

The compound (I) can be obtained by reacting compound (IX) with compound(X) in the presence of a palladium catalyst. The palladium catalyst tobe used for the reaction is exemplified by nonvalent and divalentpalladium complexes such as tetrakistriphenylphosphine palladium,1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium and the like. Thereaction temperature is in the range of from 0° C. to 150° C.,preferably from 50° C. to 120° C. The reaction time is about 1 hour to48 hours. The reaction is usually carried out in a solvent that does notaffect the reaction. Examples of the solvent that does not affect thereaction include ether such as dimethoxyethane, dioxane, tetrahydrofuran(THF) and the like, alcohol such as methanol, ethanol and the like,halogenated hydrocarbon such as dichloromethane, chloroform and thelike, aromatic hydrocarbon such as benzene, toluene and the like, waterand the like, which may be used alone or combination of one or two ormore kinds of these at a suitable mixing ratio. When compound (X) is aboron compound, a base (sodium carbonate etc.) is preferably present inthe reaction system.

[Step J]

When R of compound (I) is a protecting group, the protecting group iseliminated by a method known per se or a method similar thereto to givecompound (I′). For example, when R is a trityl group, it can be removedby a treatment under acidic conditions or by hydrogenolysis. Examples ofthe acid include organic acid such as formic acid, acetic acid and thelike, inorganic acid such as hydrochloric acid and the like, and thelike. A solvent inert to the reaction, such as alcohol, ether such asTHF and the like, can be also used. The reaction temperature isgenerally from 0° C. to −100° C.

When the desired compound is obtained in a free form by the abovereactions, the compound may be converted to a salt by a conventionalmethod. When the desired compound is obtained as a salt, the compoundcan be converted to a free form or a different salt by a conventionalmethod. Compounds (I) and (I′) thus obtained can be isolated from thereaction mixture and purified by a known procedure such as phasetransfer, concentration, solvent extraction, fractional distillation,crystallization, recrystallization, chromatography and the like.

In addition, a protecting group may be used for amino group, carboxylgroup, hydroxy group and the like in the compound or a salt thereof tobe reacted in the above reactions, which are not involved in thereaction. A protecting group may be added or eliminated by a knownmethod.

Examples of the protecting group of amino group include C₁₋₆alkylcarbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl, C₁₋₆alkyl-oxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl etc.),phenyloxycarbonyl, C₇₋₁₀ aralkyloxycarbonyl (e.g., phenyl-C₁₋₄alkyloxy-carbonyl such as benzyloxycarbonyl etc., and the like), trityl,phthaloyl and N,N-dimethylaminomethylene and the like, each of which maybe substituted, and formyl. Examples of the substituent include halogenatom (e.g., fluorine, chlorine, bromine, iodine etc.), formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, valeryl etc.), nitro group andthe like. The number of substituent is about 1 to 3.

Examples of the protecting group of carboxyl group include, C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl etc.),phenyl, trityl, silyl and the like, each of which may be substituted.Examples of the substituent include halogen atom (e.g., fluorine,chlorine etc.), formyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl,valeryl etc.), nitro group and the like. The number of substituent isabout 1 to 3.

Examples of the protecting group of hydroxy group include C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl etc.),phenyl, C₇₋₁₀ aralkyl (e.g., phenyl-C₁₋₄ alkyl such as benzyl etc., andthe like), formyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl etc.),phenyloxycarbonyl, benzoyl, (C₇₋₁₀ aralkyloxy)carbonyl (e.g.,phenyl-C₁₋₄ alkyloxy-carbonyl such as benzyloxycarbonyl etc., and thelike), pyranyl, furanyl, silyl and the like, each of which may besubstituted. Examples of the substituent include halogen atom (e.g.,fluorine, chlorine etc.), C₁₋₆ alkyl (e.g., methyl, ethyl, propyl etc.),phenyl, C₇₋₁₀ aralkyl (e.g., phenyl-C₁₋₄ alkyl such as benzyl etc.),nitro group and the like. The number of substituent is about 1 to 4.

The protection group can be eliminated by a method known per se or asimilar method. Examples of the method include treating using, forexample, acid, base, reduction, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate and the like.

The compound (I) has a superior effect as a medicine, and especially hasa superior inhibitory activity against steroid C_(17,20)-lyase. Thecompound (I) is low toxic and causes few side effects. Therefore,compound (I) is useful as, for example, (i) an androgen or estrogenreducer, and (ii) an agent for the prophylaxis or treatment of variousandrogen- or estrogen-related diseases, such as (1) primary cancer,metastasis or recurrence of malignant tumor (e.g., prostate cancer,breast cancer, uterine cancer, ovarian cancer etc.), (2) varioussymptoms accompany these cancers (e.g., pain, cachexia etc.), (3)prostatic hypertrophy, virilism, hirsutism, male pattern alopecia,precocious puberty, endometriosis, uterus myoma, adenomyosis of uterus,mastopathy, polycystic ovary syndrome etc. in a mammal (e.g., human,bovine, horse, pig, dog, cat, monkey, mouse, rat etc., especiallyhuman).

While compound (I) has a superior effect even when used solely, theeffect can be further promoted by using the compound in combination withother pharmaceutical preparations and therapies. Examples of thepreparation and therapy to be combined include, but not limited to, sexhormones, alkylating agents, antimetabolites, antitumor antibiotics,plant alkaloids, immunotherapies and the like.

Examples of hormone-related agent include fosfestrol,diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate,megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol,allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene,levormeloxifene, antiestrogens (e.g., tamoxifen citrate, toremifenecitrate etc.), contraceptive pill, mepitiostane, testolactone,aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin,leuprorelin etc.), LH-RH antagonists (e.g., ganirelix, cetrorelix,abarelix etc.), droloxifene, epitiostanol, ethinylestradiol sulfonate,aromatase inhibitors (e.g., fadrozole, anastrozole, letrozole,exemestane, vorozole, formestane etc.), anti-androgens (e.g., flutamide,bicalutamide, nilutamide etc.), 5α-reductase inhibitors (e.g.,finasteride, epristeride etc.), adrenocortical hormones (e.g., cortisol,dexamethasone, prednisolone, betamethasone, triamcinolone etc.),inhibitors of androgen-synthesis (e.g., abiraterone etc.), retinoid andsuppressing agents of retinoid metabolism (e.g., liarozole etc.), andthe like.

Examples of alkylating agents include nitrogen mustard, nitrogen mustardN-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide,thiotepa, carboquone, improsulphan tosilate, busulfan, nimustinehydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine,estramustine phosphate sodium, triethylenemelamine, carmustine,lomustine, streptozocin, pipobroman, ethoglucid, carboplatin, cisplatin,miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine,dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa,ribomustin, temozolomide, treosulfan, trofosfamide, zinostatinstimalamer, adozelesin, cystemustine, bizelesin, and the like.

Examples of antimetabolites include, for example, mercaptopurine,6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine,cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FUanalogues (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,galocitabine, emitefur etc.), aminopterin, leucovorin calcium, tabloid,butocin, calcium folinate, calcium levofolinate, cladribine,fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim,idoxuridine, mitoguazone, tiazofurin and the like.

Example of antitumor antibiotics include actinomycin D, actinomycin C,mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate,peplomycin sulfate, daunorubicin hydrochloride, doxorubicinhydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride,epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin,carzinophilin, mitotane, zorubicin hydrochloride, mitoxantronehydrochloride, idarubicin hydrochloride, and the like.

Examples of plant alkaloid include etoposide, etoposide phosphate,vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide,paclitaxel, vinorelbine, and the like.

Examples of immunotherapeutic agent (BRM) include picibanil, krestin,sizofiran, lentinan, ubenimex, interferons, interleukins,macrophage-colony stimulating factor, granulocyte-colony stimulatingfactor, erythropoietin, lymphotoxin,-BCG vaccine, corynebacteriumparvum, levamisole, polysaccharide-K, procodazol, and the like.

In addition, L-asparaginase, aceglatone, procarbazine hydrochloride,cobalt-protoporphyrin complex, mercury-hematoporphyrin sodium salt,topoisomerase I inhibitors (e.g., irinotecan, topotecan etc.),topoisomerase II inhibitors (e.g., sobuzoxane etc.), differentiationpromoter (e.g., retinoid, vitamin D etc.), inhibitor of proliferationfactor (e.g., suramin etc.), antibodies (e.g., herceptin etc.),angiogenesis inhibitors, α-blocker (e.g., tamsulosin hydrochlorideetc.), tyrosin kinase inhibitors, and the like can be used.

Together with the chemotherapy including administration of compound (I),therapies other than chemotherapies, such as an operation includingorchidectomy, thermotherapy, radiotherapy and the like can be conducted.

Particularly, the compound of the present invention can remove androgensor estrogens in blood more effectively by combinedly using a LH-RHmodulator such as LH-RH agonist (e.g., goserelin acetate, buserelin,leuprorelin etc.) and LHRH antagonist (e.g., ganirelix, cetrorelix,abarelix etc.).

Thus, the compound of the present invention has high selectivity tosteroid C_(17,20)-lyase, and reduces androgen concentration withoutaffecting drug metabolizing enzyme such as CYP3A4 and the like.

Examples of the pharmaceutically acceptable carrier include variousorganic or inorganic carriers conventionally used as materials forpharmaceuticals, which are added as appropriate in suitable amounts asexipients, lubricants, binders, disintegrators, thickeners for solidpreparations; solvents, dispersants, solbilizing agents, suspendingagents, isotonic agents, buffer agents, soothing agents for liquidpreparations, and the like. Where necessary, additives such aspreservatives, antioxidants, coloring agents, sweetening agents etc. canbe used. Examples of preferable exipient include lactose, saccharose,D-mannitol, starch, crystalline cellulose, light anhydrous silicic acidand the like. Examples of preferable lubricant include magnesiumstearate, calcium stearate, talc, colloidal silica, and the like.Examples of preferable binder include crystalline cellulose, saccharose,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinyl pyrrolidone, and the like.Examples of preferable disintegrator include starch,carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcrosscarmelose, sodium carboxymethyl starch, and the like. Examples ofpreferable thickener include natural rubbers, cellulose derivatives,acrylate polymers, and the like. Examples of preferable solvent includewater for injection, alcohol, propyleneglycol, Macrogol, sesame oil,corn oil, and the like. Examples of preferable dispersant include Tween80, HCO 60, polyethylene glycol, carboxymethylcellulose, sodiumalginate, and the like. Examples of preferable solbilizing agent includepolyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, and the like. Examples of preferablesuspending agent include surfactants, such as stearyl triethanolamine,sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkoniumchloride, benzethonium chloride, glycerin monostearate etc.; hydrophilicpolymer such as polyvinyl alcohol, polyvinyl pyrrolidone, sodiumcarboxymethyl cellulose, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose etc.; and the like.Examples of preferable isotonic agent include sodium chloride, glycerin,D-mannitol and the like.

Examples of preferable buffer agent include buffer solution such asphosphate, acetate, carbonate, citrate etc., and the like. Examples ofpreferable soothing agent include benzyl alcohol, and the like. Examplesof preferable preservative include paraoxybenzoates, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, andthe like. Examples of preferable antioxidant include sulfurous acidsalt, ascorbic acid, and the like.

The pharmaceutical composition and pharmaceutical preparation of thepresent invention can be manufactured by a conventional method. Theratio of compound (I) contained in a pharmaceutical preparation isusually 0.1 to 100% (w/w). Specific examples are shown below.

(1) Tablets, Powder, Granules, Capsules

These can be produced by adding, for example, exipients, disintegrators,binders, lubricants etc. to compound (I), compression forming themixture and, where necessary, coating for masking of taste, enteric orsustained release.

(2) Injection

This can be produced by preparing compound (I) into an aqueous injectiontogether with, for example, dispersants, preservatives, isotonic agentsetc., or into an oily injection by dissolving, suspending or emulsifyingthe compound in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil etc., or propylene glycol etc.

(3) Suppository

This can be produced by preparing compound (I) into an oily or aqueoussolid, semisolid or liquid composition. Examples of oily base used forthe composition include glyceride of higher fatty acid (e.g., cacaobutter, witepsols etc.), middle fatty acid (e.g., migriols etc.),vegetable oils (e.g., sesame oil, soybean oil, cotton seed oil etc.) andthe like. Examples of aqueous gel base include natural rubber, cellulosederivative, vinyl polymer, acrylate polymer, and the like.

The content of compound (I) admixed in these preparations is usually0.01 to 50%, though subject to change depending upon the kind ofpreparations.

While the amount of compound (I) to be contained in the above-mentionedpharmaceutical preparation varies depending upon the compound selected,the kind of animal to be the administration target, administrationfrequency and the like, the compound proves effective over a broadrange. The daily dose of the pharmaceutical preparation of the presentinvention as an effective amount of compound (I) of the presentinvention, for example, for in the case of oral administration to anadult patient with a solid tumor (e.g., patient with prostate cancer) isgenerally about 0.001 to about 500 mg/kg body weight, preferably about0.05 to about 40 mg/kg body weight, more preferably about 0.1 to about10 mg/kg body weight. When the compound is parenterally administered oradministered concurrently with a different anticancer agent, the dosegenerally becomes less than those mentioned above. The amount of thecompound actually administered is determined according to the selectionof compound, dosage form of each preparation, age, body weight and sexof patient, degree of disease, administration route, period andintervals of administration and the like, which can be varied accordingto the judgement of a doctor.

The administration route of the aforementioned pharmaceuticalpreparation is free of any particular limitaion by various conditions.The preparation can be administered, for example, orally orparenterally. Examples of the “parenteral” used here includeintravenous, intramuscular, subcutaneous, intranasal, intradermal,instillation, intracerebral, intrarectal, intravaginal andintraperitoneal administrations, and the like.

The above-mentioned administration term and administration interval varydepending upon various conditions and determined any time by judgementof a doctor. Divided administration, consecutive administration,intermittent administration, high dose short period administration,repeat administration and the like can be employed. For oraladministration, for example, the dose is desirably given once a day ordivided into several portions (especially two or three doses a day) andadministered. Administration of a sustained release preparation orintravenous drip infusion over a long time is also possible.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention is described in more detail by means of thefollowing Examples, Formulation Example and Experimental Examples. TheseExamples are mere practice of the invention and do not limit the presentinvention. They can be modified as long as they do not deviate from thescope of the present invention. In the Examples, abbreviations mean thefollowing.

s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt:double triplet, m: multiplet, br: broad, J: coupling constant, roomtemperature: 0-30° C., DMF: dimethylformamide, THF: tetrahydrofuran.

EXAMPLES Reference Example 1 Production of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid

To a solution of p-dibromobenzene (66.0 g) in THF (700 ml) was addeddropwise a solution (1.6 M; 180 ml) of n-butyllithium in hexane at —78°C., and the mixture was stirred at the same temperature for 15 min. Asolution of 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanone (85.0 g)in THF (250 ml) was added dropwise, and the mixture was further stirredfor 15 min. To the reaction mixture was added dropwise a solution (1.6M; 270 ml) of n-butyllithium in hexane at −78° C., and the mixture wasstirred at the same temperature for 15 min, which was followed byaddition of trimethyl borate (196 ml). The reaction mixture was stirredat room temperature for 2 h, and an aqueous ammonium chloride solutionwas added. The mixture was stirred at room temperature for 12 h, and theorganic layer was separated, washed with 1N sodium hydroxide and brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedto give a crude product (126 g) of the title compound as an amorphouspowder. This product was used in a reaction without purification.

Example 1 Production of1-(1H-imidazol-4-yl)-1-(4′-methoxy-[1,1′-biphenyl]-4-yl)-2-methyl-1-propanol(i) Production of 4-bromo-4′-methoxy-1,1′-biphenyl

Under an argon atmosphere, p-dibromobenzene (9.99 g),4-methoxyphenylboronic acid (2.03 g) and tetrakistriphenylphosphinepalladium (497 mg) were dissolved in dimethoxyethane (20 ml). A 2Maqueous sodium carbonate solution (20 ml) was added and the mixture washeated under reflux for 14 h. The reaction mixture was cooled to roomtemperature and the precipitated crystals were collected by filtration.The obtained crystals were dissolved in ethyl acetate and insolublematerials were filtered off. The solvent was evaporated and the obtainedsolid was washed with hexane to give the title compound (2.09 g) as acolorless solid.

¹H-NMR (CDCl₃) δ: 3.84 (3H, s), 6.97 (2H, d, J=8.8 Hz), 7.37-7.56 (6H,m).

IR (KBr): 1483, 1291, 1258, 1038, 812 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(4′-methoxy-[1,1′-biphenyl]-4-yl)-2-methyl-1-propanol

4-Bromo-4′-methoxy-1,1′-biphenyl (1.95 g) was dissolved in THF (40 ml)and the mixture was cooled to −78° C. A solution (1.6 M; 5.5 ml) ofn-butyllithium in hexane was added dropwise, and the mixture was stirredat −78° C. for 1 h. Then, a solution (10 ml) of1-(1H-imidazol-4-yl)-2-methyl-1-propanone (335 mg) in THF was slowlyadded dropwise. The reaction mixture was heated from −78° C. to roomtemperature and saturated aqueous ammonium chloride solution was addedto the reaction mixture. The mixture was extracted with ethyl acetateand the organic layer was dried and concentrated. The obtained residuewas recrystallized from ethyl acetate to give the title compound (322mg) as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz),2.52-2.76 (1H, m), 3.85 (3H, s), 6.92-7.02 (3H, m), 7.38-7.62 (7H, m).

IR (KBr): 3218, 1497; 1252, 1038, 1007, 816 cm⁻¹.

Example 2 Production of1-[1,1′-biphenyl]-4-yl-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 1-(ii) using4-bromo-1,1′-biphenyl (5.17 g), the title compound (1.76 g) was obtainedas a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=6.8 Hz), 0.99 (3H, d, J=6.8 Hz),2.57-2.74 (1H, m), 6.98 (1H, d, J=1.2 Hz), 7.30-7.47 (3H, m), 7.50-7.65(7H, m).

IR (KBr): 3142, 2965, 1487, 826, 762 cm⁻¹.

Example 3 Production of1-(1H-imidazol-4-yl)-1-(2′-methoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-propanol(i) Production of 4-bromo-2′-methoxy-1,1′-biphenyl

By the reaction in the same manner as in Example 1-(i) using2-methoxyphenylboronic acid (3.15 g), the title compound (4.77 g) wasobtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.81 (3H, s), 6.92-7.08 (2H, m), 7.21-7.44 (4H, m),7.45-7.60 (2H, m).

IR (KBr): 1478, 1256, 1003, 754 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(2′-methoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 1-(ii) using4-bromo-2′-methoxy-1,1′-biphenyl (1.58 g), the title compound (225 mg)was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.85 (3H, d, J=7.0 Hz), 0.98 (3H, d, J=7.0 Hz),2.52-2.72 (1H, m), 3.79 (3H, s), 6.92-7.06 (3H, m), 7.26-7.36 (2H, m),7.42-7.62 (5H, m).

IR (KBr): 3073, 2967, 1487, 1260, 1238, 1005, 752 cm⁻¹.

Example 4 Production of1-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

To a solution of p-dibromobenzene (20.0 g) in diethyl ether-THF (4:1)(210 ml) was slowly added dropwise at −78° C. a solution (1.6 M; 34.6ml) of n-butyllithium inhexane. The mixture was stirred at −78° C. for40 min and at −78 to −30° C. for 15 min. A solution of2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propane (14.0 g) in THF (80 ml)was slowly added dropwise, and the mixture was stirred at −78 to −50° C.for 40 min. To the reaction mixture was added saturated aqueous ammoniumchloride solution, and the mixture was extracted with ethyl acetate, theorganic layer was washed with saturated brine and dried. The solvent wasevaporated under reduced pressure and the residue was recrystallizedfrom ethyl acetate-hexane to give the title compound (16.2 g) ascolorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.71 (3H, d, J=6.6 Hz), 0.89 (3H, d, J=6.6 Hz),2.30-2.44 (1H, m), 3.50 (1H, s), 6.72 (1H, d, J=1.2 Hz), 7.09-7.16 (6H,m), 7.30-7.38 (14H, m)

IR (KBr): 1489, 1445, 1159, 1009, 909, 812, 747, 735, 702, 660 cm⁻¹

(ii) Production of1-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

To a suspension of1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.60g), 4-fluorophenylboronic acid (1.50 g) and 2M aqueous sodium carbonatesolution (26.8 ml) in dimethoxyethane (50 ml) was addedtetrakis(triphenylphosphine)palladium(0) (387 mg). Under an argonatmosphere, the mixture was heated under reflux for 12 h. The reactionmixture was extracted with ethyl acetate-THF (8:3), washed with waterand saturated brine, and dried. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchomatography (eluent, hexane:ethyl acetate=6:1→4:1) to give the titlecompound (3.16 g) as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz),2.42-2.49 (1H, m), 3.53 (1H, s), 6.78 (1H, s), 7.06-7.15 (7H, m),7.33-7.57 (17H, m)

IR (KBr): 1493, 1445, 1223, 1159, 818, 748, 733, 702 cm⁻¹

(iii) Production of1-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

A solution (75 ml) of1-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(3.12 g) and pyridine hydrochloride (1.11 g) in methanol was stirred at60° C. for 3.5 h. The solvent was evaporated from the reaction mixtureunder reduced pressure and the residue was diluted with ethyl acetate.Saturated aqueous sodium hydrogen carbonate was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried. The solvent was evaporated under reducedpressure and the residue was purified by column chomatography (eluent,hexane:ethyl acetate=2:1→1:5) and recrystallized from ethylacetate-hexane to give the title compound (1.34 g) as colorless needlecrystals.

¹H-NMR (CDCl₃) δ: 0.85 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz),2.60-2.74 (1H, m), 3.42 (1H, br s), 7.02-7.16 (3H, m), 7.48-7.66 (7H,m), 9.16 (1H, br s)

IR (KBr): 3241, 1493, 1397, 1242, 1009, 814, 781, 762, 623, 511 cm⁻¹

Example 5 Production of1-(4′-chloro[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(4′-chloro[1,1′-biphenyl]-4-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(ii) using1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.60g), 4-chlorophenylboronic acid (1.68 g), 2M aqueous sodium carbonatesolution (26.8 ml) and tetrakis(triphenylphosphine)palladium(0) (387mg), the title compound (3.04 g) was obtained as colorless needlecrystals.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=7.0 Hz), 0.92 (3H, d, J=7.0 Hz),2.42-2.49 (1H, m), 3.53 (1H, s), 6.78 (1H, s), 7.13-7.15 (6H, m),7.32-7.59 (18H, m)

IR (KBr): 1485, 1445, 1094, 1005, 909, 812, 747, 733, 700 cm⁻¹

(ii) Production of1-(4′-chloro[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-(4′-chloro[1,1′-biphenyl]-4-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(3.00 g) and pyridine hydrochloride (1.04 g), the title compound (1.18g) was obtained as colorless plate crystals.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=7.0 Hz), 0.98 (3H, d, J=7.0 Hz),2.58-2.75 (1H, m), 3.38 (1H, br s), 7.00 (1H, s), 7.37 (2H, d, J=8.4Hz), 7.48-7.64 (7H, m), 9.24 (1H, br s)

IR (KBr): 3200, 1485, 1364, 1190, 1094, 1028, 1005, 808, 781 cm⁻¹

Example 6 Production of1-[1,1′-biphenyl]-3-yl-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 1-(ii) using3-bromo-1,1′-biphenyl (0.98 g), the title compound (0.25 g) was obtainedas a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.55-2.73 (1H, m), 6.97 (1H, d, J=1.0 Hz), 7.28-7.50 (7H, m), 7.54-7.62(2H, m), 7.72-7.77 (1H, m).

IR (KBr): 3200, 1005, 799 cm⁻¹.

Example 7 Production of1-(1H-imidazol-4-yl)-1-(2′-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol(i) Production of 3-bromo-2′-methoxy-1,1′-biphenyl

By the reaction in the same manner as in Example 1-(i) using2-methoxyphenylboronic acid (2.90 g), the title compound (4.38 g) wasobtained as a colorless oil.

¹H-NMR (CDCl₃) δ: 3.81 (3H, s), 6.97 (1H, d, J=8.2 Hz), 7.02 (1H, dt,J=1.0, 7.4 Hz), 7.21-7.49 (5H, m), 7.68 (1H, t, J=1.8 Hz).

IR (KBr): 1466, 1254, 1235, 1028 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(2′-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 1-(ii) using3-bromo-2′-methoxy-1,1′-biphenyl (2.10 g), the title compound (0.44 g)was obtained as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.85 (3H, d, J=6.8 Hz), 0.99 (3H, d, J=6.8 Hz),2.40-2.80 (1H, m), 3.77 (3H, s), 6.93-7.07 (3H, m), 7.25-7.49 (6H, m),7.63 (1H, s).

IR (KBr): 2961, 1473, 1236, 1024 cm⁻¹.

Example 8 Production of1-(1H-imidazol-4-yl)-1-(3′-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol(i) Production of 3-bromo-3′-methoxy-1,1′-biphenyl

By the reaction in the same manner as in Example 1-(i) using3-methoxyphenylboronic acid (3.04 g), the title compound (3.10 g) wasobtained as a colorless oil.

¹H-NMR (CDCl₃) δ: 3.85 (3H, s), 6.86-6.96 (1H, m), 7.04-7.17 (2H, m),7.23-7.54 (4H, m), 7.70-7.75 (1H, m).

IR (KBr): 1591, 1559, 1470, 1213 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(3′-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 1-(ii) using3-bromo-3′-methoxy-1,1′-biphenyl (2.09 g), the title compound (0.24 g)was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz),2.58-2.78 (1H, m), 3.86 (3H, s), 6.88 (1H, d, J=8.4 Hz), 7.00 (1H, s),7.08-7.24 (2H, m), 7.24-7.60 (6H, m), 7.79 (1H, s).

IR (KBr): 3202, 1472, 1044, 1005 cm⁻¹.

Example 9 Production of1-(1H-imidazol-4-yl)-1-(4′-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol(i) Production of 3-bromo-4′-methoxy-1,1′-biphenyl

By the reaction in the same manner as in Example 1-(i) using4-methoxyphenylboronic acid (3.08 g), the title compound (3.84 g) wasobtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 3.85 (3H, s), 6.92-7.02 (2H, m), 7.22-7.32 (1H, m),7.38-7.54 (4H, m), 7.69 (1H, t, J=1.9 Hz).

IR (KBr): 1520, 1474, 1252, 837 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-1-(4′-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 1-(ii) using3-bromo-4′-methoxy-1,1′-biphenyl (2.01 g), the title compound (0.50 g)was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=6.9 Hz), 0.98 (3H, d, J=6.9 Hz),2.50-2.74 (1H, m), 3.83 (3H, s), 6.89-6.99 (3H, m), 7.26-7.55 (6H, m),7.71-7.76 (1H, m).

IR (KBr): 2969, 1516, 1480, 1248, 1181 cm⁻¹.

Example 10 Production of1-(1H-imidazol-4-yl)-1-(4-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol(i) Production of 4-methoxy[1,1′-biphenyl]-3-carbaldehyde

By the reaction in the same manner as in Example 1-(i) using5-bromo-o-anisaldehyde (8.00 g), the title compound (3.75 g) wasobtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 3.98 (3H, s), 7.08 (1H, d, J=8.8 Hz), 7.28-7.48 (3H,m), 7.49-7.63 (2H, m), 7.80 (1H, dd, J=2.5, 8.8 Hz), 8.08 (1H, d, J=2.5Hz), 10.52 (1H, s).

IR (KBr): 1680, 1609, 1483, 1271 cm⁻¹.

(ii) Production of1H-imidazol-4-yl(4-methoxy[1,1′-biphenyl]-3-yl)methanol

4-Bromo-1H-imidazole (5.20 g) was dissolved in THF (50 ml) and themixture was cooled to −78° C. A solution (1.7 M; 50 ml) oft-butyllithium in pentane was added. The mixture was stirred at 0° C.for 1.5 h and cooled to −78° C. again. A solution (30 ml) of4-methoxy[1,1′-biphenyl]-3-carbaldehyde (2.54 g) in THF was added, andthe mixture was heated from −78° C. to room temperature and furtherstirred at room temperature for 24 h. Aqueous ammonium chloride solutionwas added, and the mixture was extracted with ethyl acetate. The organiclayer was dried and concentrated. The residue was purified by silica gelcolumn chomatography (eluent, dichloromethane:methanol=15:1) andrecrystallized from ethyl acetate to give the title compound (1.15 g) asa colorless solid.

¹H-NMR (CDCl₃) δ: 3.84 (3H, s), 6.15 (1H, s), 6.70 (1H, s), 6.96 (1H, d,J=8.4 Hz), 7.23-7.44 (3H, m), 7.46-7.57 (4H, m), 7.69 (1H, d, J=2.2 Hz).

IR (KBr): 3134, 1481, 1242, 1030 cm⁻¹.

(iii) Production of(1H-imidazol-4-yl)(4-methoxy[1,1′-biphenyl]-3-yl)methanone

1H-Imidazol-4-yl(4-methoxy[1,1′-biphenyl]-3-yl)methanol (0.94 g) wasdissolved in dichloromethane (100 ml) and manganese dioxide (5.52 g) wasadded. The mixture was stirred at room temperature for 14 h, filtratedand concentrated. To the obtained residue was added ethyl acetate andthe mixture was crystallized to give the title compound (0.84 g) as acolorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.87 (3H, s), 7.11 (1H, d, J=8.4 Hz), 7.28-7.49(3H, m), 7.51-7.60 (3H, m), 7.67-7.76 (2H, m), 7.83 (1H, m).

IR (KBr): 3000, 1636, 1483, 1273 cm⁻¹.

(vi) Production of1-(1H-imidazol-4-yl)-1-(4-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol

1H-Imidazol-4-yl(4-methoxy[1,1′-biphenyl]-3-yl)methanone (0.62 g) wasdissolved in THF (15 ml) and the mixture was cooled to −40° C. Asolution (0.6 M; 15 ml) of isopropyl magnesium chloride in THF wasslowly added dropwise and the mixture was warmed to room temperature.The mixture was stirred for 1 h and thereto was added saturated aqueousammonium chloride solution. The mixture was diluted with water andextracted with ethyl acetate. The extract was dried and concentrated.The obtained residue was purified by silica gel column chomatography(eluent, dichloromethane:methanol=40:1) to give the colorless amorphoustitle compound (0.16 g).

¹H-NMR (CDCl₃) δ: 0.92 (3H, d, J=6.6 Hz), 0.95 (3H, d, J=6.6 Hz),2.70-2.95 (1H, m), 3.90 (3H, s), 6.97 (1H, d, J=8.6 Hz), 7.06 (1H, s),7.24-7.56 (7H, m), 7.73 (1H, d, J=1.8 Hz).

IR (KBr): 2967, 1481, 1242, 1024 cm⁻¹.

Example 11 Production of1-(1H-imidazol-4-yl)-1-(6-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol(i) Production of 6-methoxy[1,1′-biphenyl]-3-carbaldehyde

By the reaction in the same manner as in Example 1-(i) using3-bromo-p-anisaldehyde (7.98 g), the title compound (7.78 g) wasobtained as a colorless oil.

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 7.09 (1H, d, J=9.2 Hz), 7.30-7.56 (5H,m), 7.85 (1H, s), 7.87 (1H, dd, J=2.2, 7.8 Hz), 9.93 (1H, s).

IR (KBr): 1694, 1595, 1265, 1175 cm⁻¹.

(ii) Production of(1H-imidazol-4-yl)(6-methoxy[1,1′-biphenyl]-3-yl)methanol

By the reaction in the same manner as in Example 10-(ii) using6-methoxy[1,1′-biphenyl]-3-carbaldehyde (3.10 g), the title compound(3.84 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.81 (3H, s), 5.81 (1H, s), 6.73 (1H, s), 6.97(1H, d, J=8.8 Hz), 7.24-7.46 (5H, m), 7.46-7.58 (2H, m), 7.59 (1H, d,J=1.0 Hz).

IR (KBr): 2996, 1487, 1175, 1022, 986 cm⁻¹.

(iii) Production of(1H-imidazol-4-yl)(6-methoxy[1,1′-biphenyl]-3-yl)methanol

By the reaction in the same manner as in Example 10-(iii) using(1H-imidazol-4-yl) (6-methoxy[1,1′-biphenyl]-3-yl)methanol (3.74 g), thetitle compound (2.64 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 3.92 (3H, s), 7.10 (1H, d, J=8.8 Hz), 7.35-7.60(5H, m), 7.73 (1H, s), 7.83 (1H, s), 7.90-8.10 (2H, brs).

IR (KBr): 3004, 1644, 1343, 1264 cm⁻¹.

(vi) Production of1-(1H-imidazol-4-yl)-1-(6-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 10-(iv) using(1H-imidazol-4-yl)(6-methoxy[1,1′-biphenyl]-3-yl)methanome (1.10 g), thetitle compound (0.48 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.84 (3H, d, J=6.8 Hz), 0.96 (3H, d, J=6.8 Hz),2.45-2.70 (1H, m), 3.77 (3H, s), 6.86-6.96 (2H, m), 7.26-7.56 (8H, m).

IR (KBr): 2969, 1505, 1487, 1264 cm⁻¹.

Example 12 Production of1-(4′-chloro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 1-(ii) using1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanone (34.90 g) andO-dibromobenzene (50.7 g), the title compound (37.7 g) was obtained as acolorless solid.

¹H-NMR (CDCl₃) δ: 0.72 (3H, d, J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz),2.22-2.44 (1H, m), 6.73 (1H, d, J=1.6 Hz), 7.06-7.19 (7H, m), 7.26-7.39(11H, m), 7.46 (1H, dt, J=7.8, 1.3 Hz), 7.59 (1H, t, J=1.8 Hz).

IR (KBr): 1493, 1472, 1445, 702 cm⁻¹.

(ii) Production of1-(4′-chloro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 1-(i) using4-chlorophenylboronic acid (0.49 g) and1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.04 g), the title compound (0.77 g) was obtained as a coloress solid.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.7 Hz), 0.94 (3H, d, J=6.7 Hz),2.35-2.55 (1H, m), 6.78 (1H, d, J=1.4 Hz), 7.05-7.60 (23H, m), 7.65 (1H,s).

IR (KBr): 1493, 1476, 1445, 909 cm⁻¹.

(iii) Production of1-(4′-chloro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(4′-Chloro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.71 g) and pyridine hydrochloride (0.25 g) were dissolved in methanol(20 ml), and the mixture was stirred at 60° C. for 2 h. To the reactionmixture was added saturated aqueous sodium hydrogen carbonate solutionand the mixture was concentrated. Water and ethyl acetate were added andthe mixture was extracted with ethyl acetate. The organic layer wasdried and concentrated, and the obtained residue was purified by silicagel column chomatography (eluent, dichloromethane:methanol=40:1).Recrystallization from hexane-ethyl acetate gave the title compound(0.31 g) as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz),2.50-2.78 (1H, m), 6.99 (1H, d, J=1.0 Hz), 7.33-7.44 (4H, m), 7.45-7.56(4H, m), 7.78 (1H, s).

IR (KBr): 2969, 1476, 1092, 1013 cm⁻¹.

Example 13 Production of1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(4′-fluoro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 1-(i) using4-fluorophenylboronic acid (0.41 g) and1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.01 g), the title compound (0.71 g) was obtained as a pale-yellowsolid.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.8 Hz),2.35-2.52 (1H, m), 6.78 (1H, d, J=1.0 Hz), 7.04-7.18 (8H, m), 7.22-7.38(12H, m), 7.44-7.55 (3H, m), 7.63 (1H, s).

IR (KBr): 1512, 1480, 1233, 1159 cm⁻¹.

(ii) Production of1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-(4′-fluoro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.62 g), the title compound (0.27 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz),2.40-2.80 (1H, m), 6.70-7.16 (3H, m), 7.30-7.59 (6H, m), 7.72 (1H, s).

IR (KBr): 3187, 1514, 1236, 1005, 795 cm⁻¹.

Example 14 Production of1-(2′,4′-dichloro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(2′,4′-dichloro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 1-(i) using2,4-dichlorophenylboronic acid (0.55 g) and1-(3bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.00g), the amorphous title compound (0.85 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.8 Hz),2.30-2.52 (1H, m), 6.74 (1H, d, J=1.4 Hz), 7.04-7.50 (16H, m), 7.57 (1H,dt, J=7.8, 1.5 Hz).

IR (KBr): 1493, 1464, 1445, 1165 cm⁻¹.

(ii) Production of1-(2′,4′-dichloro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 12-(iii) using1-(2′,4′-dichloro[1,1′-biphenyl]-3-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.80 g), the amorphous title compound (0.30 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.7 Hz), 0.97 (3H, d, J=6.7 Hz),2.45-2.70 (1H, m), 6.94 (1H, s), 7.12-7.60 (8H, m).

IR (KBr): 2969, 1466, 1103 cm⁻¹.

Example 15 Production of1-[2′-(dimethoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-carbaldehyde

By the reaction in the same manner as in Example 1-(i) using2-formylphenylboronic acid (0.50 g) and1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.02 g), the amorphous title compound (0.93 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.7 Hz), 0.93 (3H, d, J=6.7 Hz),2.30-2.55 (1H, m), 6.73 (1H, d, J=1.4 Hz), 7.05-7.69 (23H, m), 8.03 (1H,dd, J=1.4, 7.8 Hz), 9.92 (1H, d, J=0.8 Hz).

IR (KBr): 1692, 1597, 1493, 1447 cm⁻¹.

(ii) Production of1-[2′-(dimethoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 12-(iii) using3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-carbaldehyde(0.89 g), the amorphous title compound (0.28 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=6.7 Hz), 0.97 (3H, d, J=6.7 Hz),2.45-2.70 (1H, m), 3.10-3.40 (6H, m), 5.13 (1H, s), 6.93 (1H, m),7.10-7.75 (9H, m).

IR (KBr): 2969, 1472, 1092, 1073 cm⁻¹.

Example 16 Production of1-[3′-(dimethoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carbaldehyde

By the reaction in the same manner as in Example 1-(i) using3-formylphenylboronic acid (0.45 g) and1-(3bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.05g), the amorphous title compound (0.80 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.8 Hz), 0.95 (3H, d, J=6.8 Hz),2.35-2.58 (1H, m), 6.79 (1H, d, J=1.6 Hz), 7.07-7.64 (20H, m), 7.74-7.90(3H, m), 8.06 (1H, t, J=1.7 Hz), 10.07 (1H, s).

IR (KBr): 1698, 1445, 1163 cm⁻¹.

(ii) Production of1-[3′-(dimethoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 12-(iii) using3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carbaldehyde(0.70 g), the title compound (0.27 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.7 Hz), 0.99 (3H, d, J=6.7 Hz),2.50-2.77 (1H, m), 3.37 (6H, m), 5.42 (1H, s), 6.93-7.01 (1H, m),7.28-7.60 (7H, m), 7.66 (1H, s), 7.81 (1H, d, J=1.6 Hz).

IR (KBr): 2967, 1198, 1107, 1055 cm⁻¹.

Example 17 Production of1-(1H-imidazol-4-yl)-2-methyl-1-(2′-methyl[1,1′-biphenyl]-3-yl)-1-propanol(i) Production of2-methyl-1-(2′-methyl[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 1-(i) usingo-tolylboronic acid (0.69 g) and1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.01 g), the amorphous title compound (0.61 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.7 Hz), 0.92 (3H, d, J=6.7 Hz), 2.18(3H, s), 2.30-2.55 (1H, m), 6.73 (1H, d, J=1.4 Hz), 7.05-7.39 (23H, m),7.54 (1H, dt, J=7.8, 1.2 Hz).

IR (KBr): 1493, 1474, 1445, 1161 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-(2′-methyl[1,1′-biphenyl]-3-yl)-1-propanol

By the reaction in the same manner as in Example 12-(iii) using2-methyl-1-(2′-methyl[1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.55 g), the amorphous title compound (0.20 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz), 2.19(3H, s), 2.48-2.70 (1H, m), 6.85-6.97 (1H, m), 7.10-7.54 (9H, m).

IR (KBr): 2970, 1474, 909 cm⁻¹.

Example 18 Production of1-(1H-imidazol-4-yl)-2-methyl-1-(4′-methyl[1,1′-biphenyl]-3-yl)-1-propanol(i) Production of2-methyl-1-(4′-methyl[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 1-(i) usingp-tolylboronic acid (0.45 g) and1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.03 g), the title compound (0.76 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.7 Hz), 0.93 (3H, d, J=6.7 Hz),2.35-2.55 (1H, m), 2.40 (3H, s), 6.79 (1H, d, J=1.4 Hz), 7.06-7.54 (23H,m), 7.66 (1H, t, J=1.6 Hz).

IR (KBr): 1493, 1480, 1445, 1163 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-(4′-methyl[1,1-biphenyl]-3-yl)-1-propanol

By the reaction in the same manner as in Example 12-(iii) using2-methyl-1-(4′-methyl[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.61 g), the title compound (0.23 g) was obtained as a colorless solid.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz), 2.38(3H, s), 2.55-2.75 (1H, m), 6.98 (1H, s), 7.16-7.54 (8H, m), 7.77 (1H,t, J=1.6 Hz).

IR (KBr): 2969, 1480, 791, 735 cm⁻¹.

Example 19 Production of1-(2′,4′-difluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(2′,4′-difluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(ii) using1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (6.00g), 2,4-difluorophenylboronic acid (2.82 g), 2M aqueous sodium carbonatesolution (45 ml) and tetrakis(triphenylphosphine)palladium(0) (647 mg),the yellow amorphous title compound (6.39 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.8 Hz),2.35-2.49 (1H, m), 3.68 (1H, s), 6.76 (1H, d, J=1.4 Hz), 6.83-6.97 (2H,m), 7.09-7.16 (6H, m), 7.26-7.35 (13H, m), 7.36-7.57 (2H, m)

IR (KBr): 1508, 1480, 1447, 1140, 909, 747, 735, 702 cm⁻¹

(ii) Production of1-(2′,4′-difluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-(2′,4′-difluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(6.31 g) and pyridine hydrochloride (2.17 g), the title compound (2.93g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz),2.56-2.73 (1H, m), 6.84-6.98 (3H, m), 7.32-7.52 (5H, m), 7.69 (1H, s)

IR (KBr): 3202, 1508, 1478, 1385, 1364, 1142, 1005, 855, 845, 797 cm⁻¹

Example 20 Production of1-(3′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i)1-(3′-fluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(ii) using1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (2.62g), 3-fluorophenylboronic acid (1.09 g), 2M aqueous sodium carbonatesolution (19.5 ml) and tetrakis(triphenylphosphine)palladium(0) (281mg), the yellow amorphous title compound (2.55 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz),2.36-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J=1.2 Hz), 6.98-7.43 (22H,m), 7.55 (1H, dt, J=6.6, 2.0 Hz), 7.65 (1H, s)

IR (KBr) cm⁻¹: 1493, 1472, 1445, 1159, 909, 781, 747, 735, 702 cm⁻¹

(ii) Production of1-(3′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-(3′-fluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(2.55 g) and pyridine hydrochloride (906 mg), the title compound (1.15g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=7.0 Hz), 0.99 (3H, d, J=7.0 Hz),2.59-2.72 (1H, m), 3.52 (1H, br s), 7.00-7.06 (2H, m), 7.30-7.40 (5H,m), 7.55 (2H, br s), 7.81 (1H, br s), 9.28 (1H, br s)

IR (KBr) cm⁻¹: 3179, 1576, 1472, 1362, 1304, 1200, 1005, 777, 693 cm⁻¹

Example 21 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[4′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]-1-propanol(i) Production of2-methyl-1-[4′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 4-(ii) using1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.01g), 4-trifluoromethylphenylboronic acid (1.70 g), 2M aqueous sodiumcarbonate solution (22.4 ml) andtetrakis(triphenylphosphine)palladium(0) (323 mg), the title compound(2.58 g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=7.0 Hz), 0.94 (3H, d, J=7.0 Hz),2.45-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J=1.2 Hz), 7.09-7.14 (6H,m), 7.23-7.40 (12H, m), 7.55-7.69 (6H, m)

IR (KBr): 1447, 1327, 1167, 1125, 1073, 849, 793, 747, 735, 702 cm⁻¹

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[4′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]-1-propanol

By the reaction in the same manner as in Example 4-(iii) using2-methyl-1-[4′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(2.55 g) and pyridine hydrochloride (831 mg), the title compound (1.31g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.59-2.73 (1H, m), 3.37 (1H, br s), 7.01 (1H, s), 7.35-7.46 (2H, m),7.55-7.67 (6H, m), 7.84 (1H, s), 9.24 (1H, br s)

IR (KBr): 3252, 1327, 1171, 1119, 1073, 966, 845, 797 cm⁻¹

Example 22 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[4′-(trifluoromethoxy)[1,1′-biphenyl]-3-yl]-1-propanol(i) Production of2-methyl-1-[4′-(trifluoromethoxy)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 4-(ii) using1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.80g) 4-trifluoromethoxyphenylboronic acid (2.33 g), 2M aqueous sodiumcarbonate solution (28.3 ml) andtetrakis(triphenylphosphine)palladium(0) (408 mg), the title compound(3.67 g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=7.0 Hz), 0.94 (3H, d, J=7.0 Hz),2.36-2.50 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J=1.0 Hz), 7.10-7.16 (6H,m), 7.23-7.40 (14H, m), 7.50-7.64 (4H, m)

IR (KBr): 1493, 1481, 1445, 1264, 1225, 1165, 1015, 793, 747, 700 cm⁻¹

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[4′-(trifluoromethoxy)[1,1′-biphenyl]-3-yl]-1-propanol

By the reaction in the same manner as in Example 4-(iii) using2-methyl-1-[4′-(trifluoromethoxy)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(3.63 g) and pyridine hydrochloride (1.22 g), the title compound (3.76g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz),2.57-2.71 (1H, m), 6.98 (1H, d, J=0.8 Hz), 7.18-7.39 (4H, m), 7.51-7.59(4H, m), 7.78 (1H, s)

IR (KBr): 1510, 1478, 1271, 1227, 1167, 1105, 855, 829, 791, 708 cm⁻¹

Example 23 Production of1-[4′-fluoro-3-(methoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of 4-bromo-1-fluoro-2-(methoxymethyl)benzene

To a solution of (5-bromo-2-fluorophenyl)methanol (5.00 g) in THF (100ml) was added 60% sodium hydride (1.08 g) at 0° C., and the mixture wasstirred at room temperature for 30 min. Methyl iodide (3.80 ml) wasadded, and the mixture was stirred for 1.5 h. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate,washed with saturated brine and dried. The solvent was evaporated underreduced pressure and the residue was purified by column chomatography(eluent, hexane→hexane:ethyl acetate=50:1) to give the title compound(4.86 g) as a brown oil.

¹H-NMR (CDCl₃) δ: 3.42 (3H, s), 4.92 (2H, s), 6.93 (1H, dd, J=8.8, 8.8Hz), 7.34-7.42 (1H, m), 7.56 (1H, dd, J=2.2, 6.2 Hz)

IR (KBr): 1485, 1456, 1383, 1238, 1177, 1123, 1101, 814, 623 cm⁻¹

(ii) Production of1-[4′-fluoro-3′-(methoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol

To a solution of 4-bromo-1-fluoro-2-(methoxymethyl)benzene (4.86 g) inTHF (60 ml) was added dropwise n-butyllithium (1.6M; 15.3 ml) at −78°C., and the mixture was stirred for 40 min. Triisopropoxyborane (10.2ml) was added dropwise, and the mixture was stirred at room temperaturefor 15 h. To the reaction mixture was added 2N hydrochloric acid (20 ml)at 0° C. and the mixture was extracted with ethyl acetate, washed withsaturated brine and dried. The solvent was evaporated under reducedpressure to give a crude product (4.50 g) of4-fluoro-3-(methoxymethyl)phenylboronic acid as a yellow oil. By thereaction in the same manner as in Example 4-(ii) using this product(1.36 g),1-(3-bromophenyl)-(1-trityl-1-1H-imidazol-4-yl)-2-methyl-1-propanol(1.50 g), 2M aqueous sodium carbonate solution (11.2 ml) andtetrakis(triphenylphosphine)palladium(0) (161 mg), the yellow amorphoustitle compound (1.36 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.78 (3H, d, J=6.6 Hz), 0.96 (3H, d, J=6.6 Hz),2.43-2.50 (1H, m), 3.45 (3H, s), 4.58 (2H, s), 6.80 (1H, d, J=1.2 Hz),7.12-7.19 (7H, m), 7.28-7.52 (15H, m), 7.62 (1H, d, J=2.2, 7.0 Hz), 7.71(1H, s)

IR (KBr): 1493, 1478, 1445, 1188, 1159, 1121, 1094, 909, 748, 733, 702cm⁻¹

(iii) Production of1-[4′-fluoro-3′-(methoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-[4′-fluoro-3′-(methoxymethyl)[1,1′-biphenyl]-3-yl]-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.35 g) and pyridine hydrochloride (469 mg), the colorless amorphoustitle compound (629 mg) was obtained.

¹H-NMR (CDCl₃) δ: 0.79 (3H, d, J=6.6 Hz), 0.96 (3H, d, J=6.4 Hz),2.56-2.62 (1H, m), 3.41 (3H, s), 4.54 (2H, s), 6.88 (1H, s), 6.99-7.08(1H, m), 7.30-7.57 (6H, m), 7.73 (1H, s) IR (KBr): 2971, 1505, 1478,1385, 1229, 1192, 1123, 1092, 1007, 828, 793 cm⁻¹

Example 24 Production of1-(4′-fluoro-6-methoxy[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of 4′-fluoro-6-methoxy[1,1′-biphenyl]-3-carbaldehyde

By the reaction in the same manner as in Example 5-(ii) using3-bromo-p-anisaldehyde (14.0 g), 4-fluorophenylboronic acid (14.6 g), 2Maqueous sodium carbonate solution (260 ml) andtetrakis(triphenylphosphine)palladium(0) (3.76 g), the title compound(11.9 g) was obtained as white needle crystals.

¹H-NMR (CDCl₃) δ: 3.91 (3H, s), 7.07-7.16 (3H, m), 7.46-7.53 (2H, m),7.82-7.90 (2H, m), 9.94 (1H, s)

IR (KBr): 1694, 1599, 1497, 1265, 1225, 1177, 1020, 839, 814 cm⁻¹

(ii) Production of1-(4′-fluoro-6-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol

To a solution of 4′-fluoro-6-methoxy[1,1′-biphenyl]-3-carbaldehyde (5.00g) in THF (80 ml) was added dropwise a solution (0.63; 44.8 ml) ofisopropylmagnesium bromide in THF at 0° C., and the mixture was stirredfor 1 h 45 min. To the reaction mixture was added saturated aqueousammonium chloride solution and the mixture was extracted with ethylacetate, washed with saturated brine and dried. The solvent wasevaporated under reduced pressure and the residue was purified by columnchomatography (eluent, hexane:ethyl acetate=6:1→2:1) to give the titlecompound (3.82 g) as a yellow oil.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.6 Hz), 1.02 (3H, s, J=6.6 Hz), 1.79(1H, d, J=3.2 Hz), 1.88-2.02 (1H, m), 3.81 (3H, s), 4.35 (1H, dd, J=3.0,7.0 Hz), 6.92-7.15 (3H, m), 7.24-7.29 (2H, m), 7.44-7.53 (2H, m)

IR (KBr): 1514, 1495, 1464, 1264, 1233, 1159, 1044, 1026, 837, 814 cm⁻¹

(iii) Production of1-(4′-fluoro-6-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanone

To a solution of1-(4′-fluoro-6-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propanol (3.82 g)in dichloromethane (60 ml) was added manganese(IV) dioxide (12.1 g), andthe mixture was stirred at room temperature for 17 h. Manganese(IV)dioxide (17.7 g) was added and the mixture was stirred at roomtemperature for 1.5 h. The mixture was heated under reflux for 22 h andfiltered through Celite. The solvent was evaporated under reducedpressure to give the title compound (3.73 g) as a yellow oil.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.6 Hz), 3.55 (1H, m, J=6.6 Hz), 3.89(3H, s), 7.00-7.17 (3H, m), 7.44-7.54 (2H, m), 7.92-8.01 (2H, m)

IR (KBr): 1674, 1599, 1514, 1497, 1267, 1208, 1159, 1150, 990, 839 cm⁻¹

(iv)1-(4′-fluoro-6-methoxy[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

To a solution of 4-iodo-1H-imidazole (2.13 g) andtetramethylethylenediamine (1.66 ml) in THF (50 ml) was added dropwise asolution (3 M; 14.7 ml) of ethylmagnesium bromide in diethyl ether underice-cooling and the mixture was heated to 55° C. The mixture was stirredfor 1 h and copper(I) iodide (178 mg) was added at 40° C. The mixturewas stirred at 40-45° C. for 5 min and a solution of1-(4′-fluoro-6-methoxy[1,1′-biphenyl]-3-yl)-2-methyl-1-propane (3.73 g)in THF (20 ml) was added dropwise at 30° C. The mixture was stirred atroom temperature for 4 h. Saturated ammonium chloride was added to thereaction mixture and the mixture was extracted with ethyl acetate,washed with 5% aqueous ethylene diamine solution and saturated brine,and dried. The solvent was evaporated under reduced pressure and theresidue was purified by column chomatography (eluent, hexane:ethylacetate=1:2→ethyl acetate) to give the colorless amorphous titlecompound (922 mg).

¹H-NMR (CDCl₃) δ: 0.84 (3H, d, J=7.0 Hz), 0.96 (3H, d, J=7.0 Hz),2.54-2.67 (1H, m), 3.78 (3H, s), 6.89-17.11 (4H, m), 7.43-7.54 (5H, m)

IR (KBr): 1514, 1493, 1464, 1264, 1227, 1157, 1026, 837, 818 cm⁻¹

Example 25 Production of3′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methyl-1-propyl][1,1′-biphenyl]-4-carbonitrile(i) Production of3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propyl][1,1′-biphenyl]-4-carbonitrile

By the reaction in the same manner as in Example 4-(ii) using1-(3-bromophenyl)-(1-trityl-1-1H-imidazol-4-yl)-2-methyl-1-propanol (978mg), 4-cyanophenylboronic acid (535 mg), 2M aqueous sodium carbonatesolution (7.28 ml) and tetrakis(triphenylphosphine)palladium(0) (105mg), the title compound (622 mg) was obtained as colorless needlecrystals.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=7.0 Hz),2.40-2.47 (1H, m), 3.68 (1H, s), 6.78 (1H, d, J=1.6 Hz), 7.10-7.14 (6H,m), 7.29-7.40 (12H, m), 7.55-7.73 (6H, m)

IR (KBr): 2965, 2226, 1605, 1491, 1480, 1445, 845, 795, 754, 745, 700cm⁻¹

(ii) Production of3′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methyl-1-propyl][1,1′-biphenyl]-4-carbonitrile

By the reaction in the same manner as in Example 4-(iii) using3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propyl][1,1′-biphenyl]-4-carbonitrile(590 mg) and pyridine hydrochloride (111 mg), the title compound (261mg) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=7.0 Hz), 0.91 (3H, d, J=6.6 Hz),2.59-2.73 (1H, m), 6.99 (1H, s), 7.36-7.43 (2H, m), 7.53-7.69 (6H, m),7.83 (1H, s)

IR (KBr): 2232, 1605, 1478, 1103, 843, 791, 727, 708, 644 cm⁻¹

Example 26 Production of1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-1-ethanol (i)Production of1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-ethanol

To a solution of 3-bromo-4′-fluoro-1,1′-biphenyl (1.50 g) in THF (20 ml)was added dropwise a solution (1.6 M; 3.73 ml) of n-butyllithium inhexane at −78° C., and the mixture was stirred for 20 min. A solution of1-(1-trityl-1H-imidazol-4-yl)-1-ethanone (1.91 g) in THF (25 ml) wasadded dropwise at −78° C., and the mixture was stirred at −78° C. for 1h, at −35 to −10° C. for 1 h and at 0° C. for 1 h. Saturated aqueousammonium chloride solution was added to the reaction mixture and themixture was extracted with ethyl acetate, washed with saturated brineand dried. The solvent was evaporated under reduced pressure and theresidue was purified by column chomatography (eluent, hexane:ethylacetate=3:1→1:1) and recrystallized from ethyl acetate-hexane to givethe title compound (1.57 g) as colorless prism crystals.

¹H-NMR (CDCl₃) δ: 1.81 (3H, s), 3.44 (1H, s), 6.77 (1H, d, J=1.4 Hz),7.06-7.28 (8H, m), 7.30-7.55 (16H, m)

IR (KBr): 1514, 1483, 1441, 1221, 1163, 839, 797, 758, 750, 702 cm⁻¹

(ii) Production of1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-1-ethanol

By the reaction in the same manner as in Example 4-(iii) using1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-1-ethanol(1.51 g) and pyridine hydrochloride (599 mg), the title compound (559mg) was obtained as colorless plate crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 1.91 (3H, s), 6.89 (1H, s), 7.05-7.14 (2H, m),7.35-7.42 (3H, m), 7.48-7.55 (3H, m), 7.65 (1H, s)

IR (KBr): 3166, 1514, 1481, 1456, 1231, 1190, 1067, 833, 799, 623 cm⁻¹

Example 27 Production of1-[4′-fluoro[1,1′-biphenyl]-3-yl]-1-(1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 26-(i) using3-bromo-4′-fluoro-1,1′-biphenyl (2.80 g), a solution (1.6 M; 6.96 ml) ofn-butyllithium in hexane and 1-(1H-imidazol-4yl)-1-propanone (419 mg),the title compound (796 mg) was obtained as colorless plate crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.89 (3H, J=7.2 Hz), 2.14-2.36 (2H, m) 6.90 (1H,s), 7.05-7.14 (2H, m), 7.37-7.56 (6H, m), 7.65 (1H, s)

IR (KBr): 3191, 1512, 1235, 1181, 1096, 963, 934, 835, 799, 619 cm⁻¹

Example 28 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(2-thienyl)phenyl]-1-propanol (i)Production of2-methyl-1-[3-(2-thienyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(3-Bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.70 g) and a solution of tri-n-butyl(2-thienyl)tin (1.31 ml) in DMF(10 ml) were deaerated and tetrakis(triphenylphosphine)palladium(0) (110mg) was added. The mixture was stirred under an argon atmosphere at 80°C. for 4 h. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate, washed twice with water and then withsaturated brine, and dried. The solvent was evaporated under reducedpressure and the residue was purified by silica gel column chomatography(eluent, hexane:ethyl acetate=6:1→3:1). Recrystallization from ethylacetate-hexane gave the title compound (1.32 g) as colorless powdercrystals.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.6 Hz),2.35-2.48 (1H, m), 3.68 (1H, s), 6.79 (1H, d, J=1.0 Hz), 7.04-7.16 (6H,m), 7.24-7.35 (14H, m), 7.41-7.47 (2H, m), 7.72 (1H, s)

IR (KBr): 1493, 1445, 1165, 1003, 909, 747, 700 cm⁻¹

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(2-thienyl)phenyl]-1-propanol

By the reaction in the same manner as in Example 4-(iii) using2-methyl-1-[3-(2-thienyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.21 g) and pyridine hydrochloride (465 mg), the title compound (585mg) was obtained as colorless plate crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=7.0 Hz), 0.99 (3H, d, J=6.4 Hz),2.56-2.70 (1H, m), 6.9.8 (1H, d, J=1.2 Hz), 7.06 (1H, dd, J=3.8, 5.2Hz), 7.24-7.49 (5H, m), 7.51 (1H, d, J=1.2 Hz), 7.80 (1H, s)

IR (KBr): 3194, 2969, 1385, 1366, 1306, 1007, 822, 787, 693, 635 cm⁻¹

Example 29 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(3-thienyl)phenyl]-1-propanol (i)Production of2-methyl-1-[3-(3-thienyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

To a suspension of1-(3-bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.70 g), 3-thiopheneboronic acid (607 mg) and 2M aqueous sodiumcarbonate solution (3.16 ml) in toluene-ethanol (6:1) (17.5 ml) wasadded tetrakis(triphenylphosphine)palladium(0) (110 mg), and the mixturewas heated under reflux for 3 h under an argon atmosphere. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate, washed with saturated brine and dried. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chomatography (eluent, hexane:ethyl acetate=6:1→4:1→3:1).Recrystallization from ethyl acetate-hexane gave the title compound(1.48 g) as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz),2.36-2.49 (1H, m), 3.67 (1H, s), 6.78 (1H, d, J=1.4 Hz), 7.10-7.17 (6H,m), 7.25-7.48 (16H, m), 7.70 (1H, dd, J=1.8, 1.8 Hz)

IR (KBr): 1493, 1445, 1163, 1003, 909, 775, 747, 733, 702 cm⁻¹

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(3-thienyl)phenyl]-1-propanol

By the reaction in the same manner as in Example 4-(iii) using2-methyl-1-[3-(3-thienyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.43 g) and pyridine hydrochloride (550 mg), the title compound (585mg) was obtained as colorless plate crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=7.0 Hz), 0.98 (3H, d, J=7.0 Hz),2.57-2.70 (1H, m), 6.96 (1H, d, J=1.0 Hz), 7.28-7.48 (7H, m), 7.79 (1H,s)

IR (KBr): 3196, 2969, 1358, 1304, 1007, 801, 787, 774 cm⁻¹

Example 30 Production of1-[3-(2-furyl)phenyl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol (i)Production of1-[3-(2-furyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 28-(i) using1-(3-bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol(1.70 g), tri-n-butyl(2-furyl)tin (1.29 ml) andtetrakis(triphenylphosphine)palladium((0) (110 mg), the title compound(1.62 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.8 Hz),2.36-2.50 (1H, m), 3.67 (1H, s), 6.46 (1H, dd, J=1.8, 3.2 Hz), 6.60 (1H,d, J=3.2 Hz), 6.79 (1H, d, J=1.4 Hz), 7.10-7.15 (6H, m), 7.28-7.35 (11H,m), 7.41-7.51 (3H, m), 7.79 (1H, dd, J=1.8, 1.8 Hz)

IR (KBr): 1493, 1472, 1445, 1161, 1013, 910, 791, 733, 702, 660 cm⁻¹

(ii) Production of1-[3-(2-furyl)phenyl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-[3-(2-furyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.54 g) and pyridine hydrochloride (610 mg), the title compound (597mg) was obtained as colorless plate crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.57-2.71 (1H, m), 6.46 (1H, dd, J=1.8, 3.4 Hz), 6.65 (1H, d, J=1.8 Hz),6.98 (1H, d, J=3.4 Hz), 7.27-7.51 (5H, m), 7.85 (1H, s)

IR (KBr): 3200, 2975, 1306, 1188, 1007, 789, 729, 693, 635 cm⁻¹

Example 31 Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide(i) Production ofN-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(ii) using1-(4-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.04 g), 3-(acetylamino)phenylboronic acid (571 mg) andtetrakis(triphenylphosphine)palladium(0) (301 mg), the title compound(1.10 g) was obtained as a pale-yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz), 2.20(3H, s), 2.38-2.56 (1H, m), 3.55 (1H, s), 6.77 (1H, d, J=1.2 Hz),7.06-7.20 (6H, m), 7.24-7.76 (18H, m).

IR (KBr): 3063, 1674, 1557, 1483, 1445 cm⁻¹.

(ii) Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide(978 mg) and pyridine hydrochloride (310 mg), the title compound (276mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz),2.17 (3H, s), 2.51-2.74 (1H, m), 6.96 (1H, d, J=1.0 Hz), 7.25-7.39 (3H,m), 7.42-7.56 (5H, m), 7.68 (1H, s).

IR (KBr): 3210, 2971, 1672, 1557, 1483 cm⁻¹.

Example 32 Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-4-yl}acetamide(i) Production ofN-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-4-yl}acetamide

By the reaction in the same manner as in Example 4-(ii) using1-(4-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.00 g), 4-(acetylamino)phenylboronic acid (510 mg) andtetrakis(triphenylphosphine)palladium(0) (200 mg), the title compound(350 mg) was obtained as a colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz), 2.20(3H, s), 2.30-2.56 (1H, m), 3.53 (1H, s), 6.77 (1H, d, J=1.4 Hz),7.08-7.14 (6H, m), 7.27-7.38 (10H, m), 7.43-7.58 (8H, m).

IR (KBr): 2971, 1671, 1535, 1493 cm⁻¹.

(ii) Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-4-yl}acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-4-yl}acetamide(601 mg) and pyridine hydrochloride (0.17 g), the title compound (73 mg)was obtained as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz),2.17 (3H, s), 2.49-2.70 (1H, m), 6.96 (1H, d, J=0.8 Hz), 7.44-7.60 (9H,m).

IR (KBr): 3173, 1667, 1534, 1499 cm⁻¹.

Example 33 Production ofN-{4-fluoro-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide(i) Production of N-(5-bromo-2-fluorophenyl)acetamide

4-Bromo-1-fluoro-2-nitrobenzene (5.81 g), iron powder (6.20 g) andacetic anhydride (5 ml) were stirred in acetic acid (50 ml) at 60° C.for 16 h. Acetic acid was evaporated under reduced pressure and waterand ethyl acetate were added. The organic layer was washed with aqueoussodium hydrogen carbonate and brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was recrystallized fromhexane-ethyl acetate to give the title compound (3.56 g) as colorlessprism crystals.

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 6.87-7.03 (1H, m), 7.06-7.21 (1H, m),7.43 (1H, brs), 8.53 (1H, d, J=6.8 Hz).

IR (KBr): 3262, 1672, 1613, 1535, 1408 cm⁻¹.

(ii) Production ofN-{4-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.50 g), N-(5-bromo-2-fluorophenyl)acetamide (1.17 g) andtetrakis(triphenylphosphine)palladium(0) (0.17 g), the title compound(1.39 g); was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=7.0 Hz), 0.92 (3H, d, J=7.0 Hz), 2.24(3H, s), 3.55 (1H, s), 6.77 (1H, d, J=1.0 Hz), 7.06-7.20 (7H, m),7.20-7.36 (11H, m), 7.47 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 8.55(1H, d, J=5.2 Hz).

IR (KBr): 2960, 1680, 1545, 1493 cm⁻¹.

(iii) Production ofN-{4-fluoro-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-{4-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide(1.29 g) and pyridine hydrochloride (297 mg), the title compound (399mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.8 Hz), 0.97 (3H, d, J=6.8 Hz), 2.23(3H, s), 2.50-2.70 (1H, m), 6.95 (1H, s), 7.04-7.26 (2H, m), 7.38-7.60(5H, m), 8.47 (1H, d, J=7.8 Hz).

IR (KBr): 2971, 1682, 1669, 1609, 1487 cm⁻¹.

Example 34 Production ofN-{6-fluoro-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide(i) Production of 2-bromo-1-fluoro-4-nitrobenzene

To a mixture of 2-fluoro-5-nitroaniline (25.90 g), 47% aqueous hydrogenbromide (100 ml), water (200 ml) and acetic acid (200 ml) was addeddropwise an aqueous sodium nitrite (11.56 g) solution (100 ml), and themixture was stirred at 0° C. for 1 h. This mixture was added at 0° C. toa solution of copper bromide (CuBr: 27.30 g) dissolved in 47% aqueoushydrogen bromide (100 ml) and the mixture was stirred at roomtemperature for 16 h. The reaction mixture was extracted with ethylacetate, dried (anhydrous magnesium sulfate) and concentrated underreduced pressure. The residue was purified by silica gel chomatography(eluent: hexane). Crystallization from hexane gave the title compound(4.01 g) as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 7.22-7.35 (1H, m), 8.17-8.29 (1H, m), 8.51 (1H, dd,J=2.4, 6.0 Hz).

IR (KBr): 1537, 1470, 1348 cm⁻¹.

(ii) Production of N-(3-bromo-4-fluorophenyl)acetamide

By the reaction in the same manner as in Example 33-(i) using2-bromo-1-fluoro-4-nitrobenzene (2.27 g), iron powder (2.90 g) andacetic anhydride (2.0 ml), the title compound (2.28 g) was obtained ascolorless powder crystals.

¹H-NMR (CDCl₃) δ: 2.17 (3H, s) 7.06 (1H, t, J=8.4 Hz), 7.26-7.43 (2H,m), 7.80 (1H, dd, J=2.6, 5.6 Hz).

IR (KBr): 3306, 1669, 1609, 1549, 1493 cm⁻¹.

(iii) Production ofN-{6-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.19 g), N-(3-bromo-4-fluorophenyl)acetamide (990 mg) andtetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound(870 mg) was obtained as a pale-yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz), 2.11(3H, s), 2.30-2.58 (1H, m), 3.59 (1H, s), 6.79 (1H, d, J=1.0 Hz),6.96-7.20 (7H, m), 7.25-7.70 (15H, m), 7.88 (1H, s).

IR (KBr): 3287, 2969, 1672, 1553, 1489 cm⁻¹.

(iv) Production ofN-{6-fluoro-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-{6-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide(820 mg) and pyridine hydrochloride (230 mg), the title compound (250mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=7.0 Hz), 0.98 (3H, d, J=7.0 Hz),2.14 (3H, s), 2.56-2.70 (1H, m), 6.94-7.12 (2H, m), 7.40-7.58 (7H, m).

IR (KBr): 3158, 2973, 1667, 1489 cm⁻¹.

Example 35 Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-6-methoxy[1,1′-biphenyl]-3-yl}acetamide(i) Production of N-(3-bromo-4-methoxyphenyl)acetamide

By the reaction in the same manner as in Example 33-(i) using2-bromo-4-nitroanisole (5.41 g), iron powder (6.49 g) and aceticanhydride (4.4 ml), the title compound (4.87 g) was obtained as acolorless powder crystals.

¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 3.87 (3H, s), 6.83 (1H, d, J=8.8 Hz),7.32 (1H, brs), 7.43 (1H, dd, J=2.5, 8.8 Hz), 7.67 (1H, d, J=2.5 Hz).

IR (KBr): 3173, 1667, 1597, 1495 cm⁻¹.

(ii) Production ofN-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-6-methoxy[1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.21 g), N-(3-bromo-4-methoxyphenyl)acetamide (1.05 g) andtetrakis(triphenylphosphine)palladium(0) (0.16 g), the title compound(1.14 g) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.77 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz),2.14 (3H, s), 2.40-2.58 (1H, m), 3.77 (3H, s), 6.79 (1H, d, J=1.2 Hz),6.92 (1H, d, J=8.8 Hz), 7.06-7.20 (6H, m), 7.24-7.62 (16H, m).

IR (KBr): 2971, 1663, 1549, 1493 cm⁻¹.

(iii) Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-6-methoxy[1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-6-methoxy[1,1′-biphenyl]-3-yl}acetamide(975 mg) and pyridine hydrochloride (299 mg), the title compound (290mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz), 2.11(3H, s), 2.40-2.70 (1H, m), 3.73 (3H, s), 6.87 (1H, d, J=8.4 Hz), 6.93(1H, s), 7.24 (2H, s), 7.34 (2H, d, J=8.0 Hz), 7.41 (2H, d, J=8.0 Hz),7.50 (1H, d, J=8.4 Hz).

IR (KBr): 3183, 2973, 1667, 1495 cm⁻¹.

Example 36 Production ofN-[4′-[1-hydroxy-1-(-1H-imidazol-4-yl)-2-methylpropyl]-2-methyl[1,1′-biphenyl]-3-yl]acetamide(i) Production ofN-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-methyl[1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 33-(ii) usingN-(3-bromo-2-methyl)acetamide (1.19 g), a crude product (3.40 g) of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (5.20 ml) andtetrakis(triphenylphosphine)palladium(0) (301 mg), the colorlessamorphous title compound (1.15 g) was obtained.

¹H-NMR (CDCl₃) δ: 0,78 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz), 2.14(3H, s), 2.24 (3H, s), 2.41-2.48 (1H, m), 3.61 (1H, s), 6.77 (1H, d,J=1.4 Hz), 7.00-7.38 (20H, m), 7.50-7.54 (2H, m), 7.22 (2H, d, J=7.8Hz).

IR (KBr): 1667, 1535, 1491, 1468, 1445, 910, 733, 702 cm⁻¹.

(ii) Production ofN-[4′-[1-hydroxy-1-(-1H-imidazol-4-yl)-2-methylpropyl]-2-methyl[1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-methyl[1,1′-biphenyl]-3-yl]acetamide(1.10 g) and pyridine hydrochloride (378 mg), the colorless amorphoustitle compound (605 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=7.0 Hz), 0.97 (3H, d, J=6.6 Hz),2.05 (3H, s), 2.20 (3H, s), 2.59-2.63 (1H, m), 6.91 (1H, s), 7.03-7.19(4H, m), 7.41-7.50 (4H, m).

IR (KBr): 1665, 1535, 1468, 1439, 1372, 997, 828, 793 cm⁻¹.

Example 37 Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-5-methyl[1,1′-biphenyl]-3-yl]acetamide(i) Production ofN-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-5-methyl[1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 33-(ii) usingN-(3-bromo-5-methylphenyl)acetamide (612 mg), a crude product (1.75 g)of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (2.68 ml) andtetrakis(triphenylphosphine)palladium(0) (310 mg), the colorlessamorphous title compound (1.07 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz), 2.18(3H, s), 2.39-2.48 (4H, m), 3.56 (1H, s), 6.78 (1H, s), 7.13-7.15 (7H,m), 7.32-7.72 (17H, m).

IR (KBr): 1674, 1615, 1559, 1447, 1121, 747, 725, 700 cm⁻¹.

(ii) Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-5-methyl[1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-5-methyl[1,1′-biphenyl]-3-yl]acetamide(1.02 g) and pyridine hydrochloride (350 mg), the colorless amorphoustitle compound (410 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=7.0 Hz),2.16 (3H, s), 2.37 (3H, s), 2.60-2.66 (1H, m), 6.96 (1H, s), 7.13 (1H,s), 7.37 (1H, s), 7.46-7.50 (6H, m).

IR (KBr): 1669, 1613, 1599, 1559, 1435, 1372, 822 cm⁻¹.

Example 38 Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-5-(trifluoromethyl)[1,1′-biphenyl]-3-yl]acetamide(i) Production ofN-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-5-(trifluoromethyl)[1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 33-(ii) usingN-[3-bromo-5-(trifluoromethyl)phenyl]acetamide (1.00 g), a crude product(2.50 g) of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (3.56 ml) andtetrakis(triphenylphosphine)palladium(0) (221 mg), the colorlessamorphous title compound (1.80 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=7.0 Hz), 0.93 (3H, d, J=6.6 Hz), 2.21(3H, s), 2.42-2.49 (1H, m), 3.54 (1H, s), 6.79 (1H, d, J=1.2 Hz),7.10-7.15 (6H, m), 7.32-7.36 (10H, m), 7.45-7.64 (6H, m), 7.77 (1H, s),7.86 (1H, s).

IR (KBr): 1682, 1456, 1364, 1262, 1167, 1127, 747, 735, 702 cm⁻¹.

(ii) Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-5-(trifluoromethyl)[1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-5-(trifluoromethyl)[1,1′-biphenyl]-3-yl]acetamide(1.85 g) and pyridine hydrochloride (551 mg), the colorless amorphoustitle compound (591 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.18 (3H, s), 2.50-2.62 (1H, m), 6.98 (1H, s), 7.44-7.58 (6H, m), 7.85(2H, s).

IR (KBr): 1678, 1566, 1460, 1366, 1264, 1169, 1127, 824 cm⁻¹.

Example 39 Production ofN-[4′-[1-hydroxy-(1H-imidazol-4-yl)ethyl][1,1′-biphenyl]-3-yl]acetamide(i) Production of (4-bromophenyl) (1-trityl-1H-imidazol-4-yl)methanol

By the reaction in the same manner as in Example 4-(i) usingp-dibromobenzene (54.7 g), a solution (1.6 M; 94.7 ml) of n-butyllithiumin hexane and 1-trityl-1H-imidazole-4-carbaldehyde (34.2 g), the titlecompound (27.8 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 3.56 (1H, br s), 5.71 (2H, d, J=4.4 Hz), 6.58 (1H, s),7.07-7.13 (7H, m), 7.25-7.44 (12H, m).

IR (KBr): 1493, 1445, 1128, 1011, 909, 747, 733, 702 cm⁻¹.

(ii) Production of (4-bromophenyl) (1-trityl-1H-imidazol-4-yl)methanone

By the reaction in the same manner as in Example 24-(iii) using(4-bromophenyl)(1-trityl-1H-imidazol-4-yl)methanol (30.0 g) andmanganese dioxide (52.6 g), the title compound (23.3 g) was obtained ascolorless powder crystals.

¹H-NMR (CDCl₃) δ: 7.10-7.19 (6H, m), 7.31-7.41 (9H, m), 7.52 (1H, d,J=1.4 Hz), 7.68 (2H, d, J=8.4 Hz), 7.77 (1H, d, J=1.4 Hz), 8.21 (2H, d,J=8.4 Hz).

IR (KBr): 1644, 1520, 1213, 887, 756, 747, 702 cm⁻¹.

(iii) Production ofN-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 29-(i) using(4-bromophenyl)(1-trityl-1H-imidazol-4-yl)methanone (12.0 g),3-acetamidebenzeneboronic acid (5.66 g), 2M aqueous sodium carbonatesolution (24.3 ml) and tetrakis(triphenylphosphine)palladium(0) (842mg), the title compound (10.1 g) was obtained as colorless powdercrystals.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 7.14-7.21 (6H, m), 7.36-7.44 (12H, m),7.54-7.77 (6H, m), 8.33 (2H, d, J=8.4 Hz).

IR (KBr): 1671. 1645. 1603. 1553. 1524. 756. 702 cm⁻¹.

(iv) Production ofN-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)ethyl][1,1′-biphenyl]-3-yl]acetamide

To a solution ofN-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide(800 mg) in THF (14 ml) was added dropwise a solution (1.0 M; 4.38 ml)of methylmagnesium bromide in THF at 0° C., and the mixture was stirredat 0° C. for 20 min. Saturated ammonium chloride was added to thereaction mixture and the mixture was extracted with ethyl acetate,washed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasrecrystallized from ethyl acetate-methanol-hexane to give the titlecompound (823 mg) as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 1.81 (3H, s), 2.20 (3H, s), 3.37 (1H, s), 6.79 (1H, d,J=1.4 Hz), 7.12-7.20 (8H, m), 7.31-7.52 (16H, m), 7.65 (1H, br s).

IR (KBr): 1672, 1553, 1483, 1445, 909, 747, 733, 700 cm⁻¹.

(v) Production ofN-[4′-[1-hydroxy-(1H-imidazol-4-yl)ethyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)ethyl)[1,1′-biphenyl]-3-yl)acetamide(775 mg) and pyridine hydrochloride (286 mg), the colorless amorphoustitle compound (262 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 1.89 (3H, s), 2.16 (3H, s), 6.89 (1H, s),7.27-7.52 (8H, m), 7.69 (1H, s).

IR (KBr): 3031, 1672, 1609, 1591, 1559, 1483, 1397, 1312, 791 cm⁻¹.

Example 40 Production ofN-[4′-[cyclopropyl(hydroxy)(1H-imidazol-4-yl)methyl][1,1′-biphenyl]-3-yl]acetamide(i) Production ofN-[4′-[cyclopropyl(hydroxy)(1-trityl-1H-imidazol-4-yl)methyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 39-(iv) usingN-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide(1.50 g) and a solution (1.0 M; 9.59 ml) of cyclopropylmagnesium bromidein THF, the title compound (996 mg) was obtained as colorless powdercrystals.

1H-NMR (CDCl₃) δ: 0.41-0.49 (4H, m), 1.47-1.55 (1H, m), 2.20 (3H, s),3.26 (1H, s), 6.82 (1H, d, J=1.4 Hz), 7.11-7.41 (19H, m), 7.50-7.53 (5H,m), 7.65 (1H, s).

IR (KBr): 1671, 1591, 1559, 1483, 1445, 731, 702 cm⁻¹.

(ii) N-[4′-[cyclopropyl(hydroxy)(1H-imidazol-4-yl)methyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-[4′-[cyclopropyl(hydroxy)(1-trityl-1H-imidazol-4-yl)methyl][1,1′-biphenyl]-3-yl]acetamide(946 mg) and pyridine hydrochloride (334 mg), the colorless amorphoustitle compound (216 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.47-0.60 (4H, m), 1.57-1.64 (1H, m), 2.17 (3H,s), 7.00 (1H, s), 7.36-7.58 (8H, m), 7.71 (1H, s).

IR (KBr): 3148, 1667, 1591, 1555, 1485, 831, 791 cm⁻¹.

Example 41 Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)butyl][1,1′-biphenyl]-3-yl]acetamide(i) Production ofN-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4yl)-3-butenyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 39-(iv) usingN-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide(1.00 g) and a solution (1.0 M; 5.48 ml) of allylmagnesium bromide inTHF, the colorless amorphous title compound (909 mg) was obtained.

1H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.85 (1H, dd, J=6.2, 14.0 Hz), 3.01 (1H,dd, J=7.6, 14.0 Hz), 3.34 (1H, s), 5.04-5.11 (2H, m), 5.62-5.79 (1H, m),6.78 (1H, d, J=1.6 Hz), 7.11-7.18 (6H, m), 7.32-7.51 (18H, m), 7.65 (1H,s).

IR (KBr): 1669, 1609, 1593, 1485, 1445, 909, 747, 733, 702 cm⁻¹.

(ii) Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)butyl][1,1′-biphenyl]-3-yl]acetamide

A suspension ofN-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)-3-butenyl][1,1′-biphenyl]-3-yl]acetamide(829 mg), 10% palladium carbon (829 mg) and 1N hydrochloric acid (1.41ml) in ethanol (14 ml) was stirred under a hydrogen atmosphere at roomtemperature for 9.5 h. Sodium hydrogen carbonate (130 mg) was added andthe mixture was stirred. The reaction mixture was filtered throughCelite, and the filtrate was concentrated. The residue was purified bysilica gel chomatography(eluent;chloroform→chloroform:methanol=10:1→7:1→4:1) to give thecolorless amorphous title compound (420 mg).

¹H-NMR (CDCl₃+CD₃OD) δ: 0.90 (3H, t, J=7.0 Hz), 1.22-1.38 (2H, m),2.16-2.36 (5H, m), 6.89 (1H, s), 7.29-7.56 (8H, m), 7.71 (1H, s).

IR (KBr): 3144, 1659, 1609, 1557, 1485, 1435, 791 cm⁻¹.

Example 42 Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl]acetamide(i) Production ofN-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 39-(iv) usingN-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide(1.50 g) and a solution (3.0 M; 2.74 ml) of ethylmagnesium bromide indiethyl ether, the pale-yellow amorphous title compound (1.36 g) wasobtained.

¹H-NMR (CDCl₃) δ: 0.86 (3H, t, J=7.6 Hz), 2.12-2.20 (5H, m) 3.35 (1H,s), 6.67 (1H, s), 7.13-7.22 (6H, m), 7.26-7.48 (18H, m), 7.66 (1H, s).

IR (KBr): 1674, 1609, 1557, 1485, 1445, 747, 733, 702 cm⁻¹.

(ii) Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4yl)propyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 41-(ii) usingN-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl]acetamide(1.31 g), 10% palladium carbon (1.31 g) and 1N hydrochloric acid (2.27ml), the colorless amorphous title compound (640 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.89 (3H, t, J=7.6 Hz), 2.17-2.32 (5H, m), 6.91(1H, s), 7.30-7.53 (8H, m), 7.69 (1H, s).

IR (KBr): 3148, 1667, 1609, 1591, 1557, 1485, 831, 791 cm⁻¹.

Example 43 Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}propanamide(i) Production of N-(3-bromophenyl)propanamide

To a solution of 3-bromoaniline (5.10 g) and triethylamine (8.3 ml) inTHF (40 ml) was added dropwise propionyl chloride (2.8 ml) at 0° C. andthe mixture was stirred at 0° C. for 2 h. Water and ethyl acetate wereadded to the reaction mixture and the organic layer was separated. Theorganic layer was washed with water and brine, dried (magnesium sulfate)and concentrated under reduced pressure. The residue was recrystallizedfrom hexane-ethyl acetate to give the title compound (5.60 g) ascolorless needle crystals.

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.5 Hz), 2.39 (2H, q, J=7.5 Hz),7.11-7.30 (3H, m), 7.41 (1H, d, J=7.8 Hz), 7.79 (1H, brs).

IR (KBr): 3243, 1661, 1593, 1539 cm⁻¹.

(ii) Production ofN-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}propanamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.12 g), N-(3-bromophenyl)propanamide (1.56 g) andtetrakis(triphenylphosphine)palladium(0) (0.133 g), the title compound(1.26 g) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz), 1.25(3H, t, J=7.5 Hz), 2.30-2.50 (3H, m), 3.55 (1H, s), 6.78 (1H, s),7.08-7.44 (20H, m), 7.48 (2H, d, J=8.3 Hz), 7.54 (2H, d, J=8.3 Hz), 7.72(1H, brs).

IR (KBr): 2973, 1669, 1557, 1485 cm⁻¹.

(iii) Production ofN-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}propanamide

By the reaction in the same manner as in Example 4-(iii) usingN-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}propanamide(1.46 g) and pyridine hydrochloride (440 mg), the title compound (280mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=7.0 Hz), 0.96 (3H, d, J=7.0 Hz),1.22 (3H, t, J=7.4 Hz), 2.39 (2H, q, J=7.4 Hz), 2.40-2.70 (1H, m), 6.91(1H, d, J=1.2 Hz), 7.24-7.55 (8H, m), 7.67 (1H, s).

IR (KBr): 3196, 2975, 1669, 1557 cm⁻¹.

Example 44 Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)-3methylbutyl][1,1′-biphenyl]-3-yl]acetamide(i) Production ofN-[4′-[1-hydroxy-3-methyl-1-(1-trityl-1H-imidazol-4-yl)butyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 39-(iv) usingN-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-yl]acetamide(1.26 g) and a solution (1.0 M; 8.05 ml) of isobutylmagnesium bromide inTHF, the pale-yellow amorphous title compound (408 mg) was obtained.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.8 Hz), 0.88 (3H, d, J=6.6 Hz),1.68-1.74 (1H, m), 2.02 (2H, d, J=5.2 Hz), 2.20 (3H, s), 3.43 (1H, s),6.74 (1H, s), 7.12-7.17 (8H, m), 7.32-7.48 (16H, m), 7.65 (1H, s).

IR (KBr): 1672, 1607, 1557, 1485, 1445, 909, 747, 733, 702 cm⁻¹.

(ii) Production ofN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)-3-ethylbutyl][1,1′-biphenyl]-3-yl]acetamide

By the reaction in the same manner as in Example 41-(ii) usingN-[4′-[1-hydroxy-3-methyl-1-(1-trityl-1H-imidazol-4-yl)butyl][1,1′-biphenyl]-3-yl]acetamide(1.31 g), 10% palladium carbon (386 mg) and 1N hydrochloric acid (0.637ml), the colorless amorphous title compound (141 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.75 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz),1.66-1.78 (1H, m), 2.13-2.16 (5H, m), 6.86 (1H, s), 7.30-7.53 (8H, m),7.68 (1H, s).

IR (KBr): 1669, 1559, 1483, 1435, 1395, 1372, 791 cm⁻¹.

Example 45 Production of3′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(i) Production of 3-bromophenylcarboxamide

To a solution of 3-bromobenzoyl chloride (21.75 g) in THF (20 ml) wasadded a 40% solution (50 ml) of methylamine in methanol at 0° C. and themixture was stirred at 0° C. for 1 h. The solvent was evaporated underreduced pressure, and the residue was dissolved in ethyl acetate, themixture was washed with water and brine, dried (magnesium sulfate) andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (18.6 g) as colorlesspowder crystals.

¹H-NMR (CDCl₃) δ: 2.99 (3H, d, J=5.0 Hz), 6.55 (1H, brs), 7.28 (1H, t,J=7.9 Hz), 7.56-7.72 (2H, m), 7.91 (1H, t, J=1.8 Hz).

IR (KBr): 3304, 1640, 1557 cm⁻¹.

(ii) Production of3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 33-(ii) using3-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (1.01 g), 3-bromophenylcarboxamide (567 mg) andtetrakis(triphenylphosphine)palladium(0) (0.33 g), the title compound(435 mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz),2.36-2.58 (1H, m), 3.03 (3H, d, J=4.6 Hz), 3.66 (1H, s), 6.23 (1H, brs),6.78 (1H, d, J=1.2 Hz), 7.06-7.17 (6H, m), 7.23-7.54 (14H, m), 7.62-7.80(3H, m), 7.88-7.93 (1H, m).

IR (KBr): 3378, 2969, 1644, 1549, 1447 cm⁻¹.

(iii) Production of3′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) using3′-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(576 mg) and pyridine hydrochloride (0.22 g), the title compound (55 mg)was obtained as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz),2.60-2.84 (1H, m), 3.02 (3H, s), 7.00 (1H, d, J=1.0 Hz), 7.30-7.55 (5H,m), 7.67-7.90 (3H, m), 8.01 (1H, t, J=1.5 Hz).

IR (KBr): 2967, 2872, 1644, 1541 cm⁻¹.

Example 46 Production of4′-(1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(i)4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide.

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.44 g), 3-bromo-N-methylbenzamide (1.10 g) andtetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound(1.00 g) was obtained as a pale-yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.7 Hz), 0.93 (3H, d, J=6.7 Hz),2.30-2.54 (1H, m), 3.02 (3H, d, J=4.8 Hz), 3.58 (1H, s), 6.33 (1H, brs),6.78 (1H, d, J=1.4 Hz), 7.04-7.20 (6H, m), 7.22-7.38 (9H, m), 7.39-7.76(8H, m), 7.98 (1H, t, J=1.4 Hz).

IR (KBr): 3295, 2969, 1644, 1549, 1121 cm⁻¹.

(ii) Production of4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) using4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(850 mg) and pyridine hydrochloride (270 mg), the title compound (210mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.9 Hz), 0.98 (3H, d, J=6.9 Hz),2.40-2.80 (1H, m), 3.00 (3H, s), 6.96 (1H, s), 7.30 (1H, d, J=1.4 Hz),7.30-7.60 (5H, m), 7.60-7.74 (2H, m), 7.93 (1H, s).

IR (KBr): 3277, 2969, 1645, 1547 cm⁻¹.

Example 47 Production ofN-ethyl-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-carboxamide(i) Production of 3-bromo-N-ethylbenzamide

To a solution of sodium hydroxide (3.80 g) in methanol (50 ml)—water (15ml) was added by portions ethylamine hydrochloride (7.80 g) at 0° C. andthe mixture was stirred for 5 min. 3-Bromobenzoyl chloride (5.53 g) wasadded dropwise and the mixture was stirrd at room temperature for 1 h.Methanol was evaporated under reduced pressure, and ethyl acetate wasadded to the residue for partitioning. The organic layer was washed withwater and brine, dried (magnesium sulfate) and concentrated underreduced pressure. The residue was recrystallized from hexane-ethylacetate to give the title compound (5.47 g) as colorless powdercrystals.

¹H-NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 3.40-3.59 (2H, m), 6.11 (1H,brs), 7.30 (1H, t, J=8.2 Hz), 7.57-7.72 (2H, m), 7.90 (1H, t, J=1.4 Hz).

IR (KBr): 3308, 1638, 1541 cm⁻¹.

(ii)N-ethyl-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (7.40 g, 14.7 mmol), 3-bromo-N-ethylbenzamide (2.20 g) andtetrakis(triphenylphosphine)palladium(0) (0.441 g), the title compound(2.56 g) was obtained as a yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.8 Hz), 1.27(3H, t, J=7.2 Hz), 2.36-2.54 (1H, m), 3.42-3.61 (3H, m), 6.15 (1H, brs),6.78 (1H, d, J=1.6 Hz), 7.06-7.18 (6H, m), 7.27-7.38 (9H, m), 7.40-7.75(8H, m), 7.97 (1H, t, J=1.6 Hz).

IR (KBr): 3295, 2971, 1644, 1537 cm⁻¹.

(iii) Production ofN-ethyl-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) usingN-ethyl-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide(4.00 g) and pyridine hydrochloride (1.14 g), the title compound (664mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=6.7 Hz), 0.96 (3H, d, J=6.7 Hz),1.23 (3H, t, J=7.1 Hz), 2.48-2.70 (1H, m), 3.36-3.56 (2H, m), 6.92 (1H,d, J=1.2 Hz), 7.09 (1H, t, J=5.5 Hz), 7.35-7.56 (6H, m), 7.58-7.72 (2H,m), 7.92 (1H, t, J=1.6 Hz).

IR (KBr): 2973, 1644, 1537 cm⁻¹.

Example 48 Production of4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-isopropyl[1,1′-biphenyl]-3-carboxamide

(i) Production of 3-bromo-N-isopropylbenzamide

By the reaction in the same manner as in Example 45-(i) using3-bromobenzoyl chloride (5.70 g) and isopropylamine (4.10 g), the titlecompound (5.75 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=6.6 Hz), 4.18-4.40 (1H, m), 5.97 (1H,brs), 7.23-7.34 (1H, m), 7.55-7.71 (2H, m), 7.84-7.90 (1H, m).

IR (KBr): 3241, 2973, 1634, 1545 cm⁻¹.

(ii) Production of4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-isopropyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.40 g), 3-bromo-N-isopropylbenzamide (1.70 g) andtetrakis(triphenylphosphine)palladium(0) (0.220 g), the title compound(1.88 g) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.4 Hz), 0.93 (3H, d, J=6.4 Hz), 1.28(6H, d, J=6.6 Hz), 2.36-2.58 (1H, m), 3.56 (1H, s), 4.20-4.44 (1H, m),5.95 (1H, d, J=7.0 Hz), 6.78 (1H, d, J=1.4 Hz), 7.06-7.20 (6H, m),7.26-7.38 (10H, m), 7.42-7.74 (7H, m), 7.95 (1H, t, J=1.6 Hz).

IR (KBr): 2971, 1636, 1537 cm⁻¹.

(iii) Production of4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-isopropyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) using4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-isopropyl[1,1′-biphenyl]-3-carboxamide(1.67 g) and pyridine hydrochloride (490 mg), the title compound (480mg) was obtained as colorless powder crystals.

¹H-NMR (DMSO-d₆) δ: 0.60-1.00 (6H, m), 1.19 (6H, d, J=6.6 Hz), 2.54-2.78(1H, m), 4.00-4.26 (1H, m), 7.42-7.68 (4H, m), 7.68-7.88 (4H, m), 8.08(1H, s), 8.24-8.40 (1H, m), 11.80 (1H, brs).

IR (KBr): 3243, 2975, 1628, 1547 cm⁻¹.

Example 49 Production ofN-cyclopropyl-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-carboxamide(i) Production of 3-bromo-N-cyclopropylbenzamide

By the reaction in the same manner as in Example 45-(i) using3-bromobenzoyl chloride (5.50 g) and cyclopropylamine (4.30 g), thetitle compound (5.20 g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.56-0.68 (2H, m), 0.82-0.96 (2H, m), 2.80-2.98 (1H,m), 6.20 (1H, brs), 7.30 (1H, t, J=8.0 Hz), 7.58-7.70 (2H, m), 7.87 (1H,t, J=1.9 Hz).

IR (KBr): 3283, 1638, 1563, 1537 cm⁻¹.

(ii) Production ofN-cyclopropyl-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.40 g), 3-bromo-N-cyclopropylbenzamide (1.53 g) andtetrakis(triphenylphosphine)palladium(0) (0.290 g), the title compound(1.84 g) was obtained as a pale-yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.58-0.74 (2H, m), 0.76 (3H, d, J=6.8 Hz), 0.83-0.98(5H, m), 2.35-2.60 (1H, m), 2.81-3.01 (1H, m), 3.56 (1H, s), 6.31 (1H,brs), 6.78 (1H, d, J=1.4 Hz), 7.04-7.18 (6H, m), 7.26-7.38 (9H, m),7.39-7.74 (8H, m), 7.93 (1H, t, J=1.8 Hz).

IR (KBr): 3270, 2969, 1644, 1532 cm⁻¹.

(iii) Production ofN-cyclopropyl-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) usingN-cyclopropyl-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide(2.13 g) and pyridine hydrochloride (650 mg), the title compound (375mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.56-0.90 (7H, m), 0.96 (3H, d, J=6.6 Hz),2.44-2.70 (1H, m), 2.78-2.96 (1H, m), 6.92 (1H, s), 7.00 (1H, brs),7.31-7.57 (6H, m), 7.58-7.74 (2H, m), 7.89 (1H, s).

IR (KBr): 3183, 2969, 1645, 1532 cm⁻¹.

Example 50 Production of4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-6-methoxy-N-methyl[1,1′-biphenyl]-3-carboxamide(i) Production of4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-6-methoxy-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 33-(ii) using3-bromo-4-methoxy-N-methylbenzamide (934 mg), a crude product (2.50 g)of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (3.83 ml) andtetrakis(triphenylphosphine)palladium(0) (221 mg), the colorlessamorphous title compound (1.45 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.78 (3H, d, J=7.0 Hz), 0.93 (3H, d, J=7.0 Hz),2.42-2.49 (1H, m), 3.00 (3H, d, J=4.8 Hz), 3.56 (3H, s), 3.85 (3H, s),6.10 (1H, br s), 6.78 (1H, d, J=1.0 Hz), 6.99 (1H, d, J=8.4 Hz),7.13-7.16 (5H, m), 7.32-7.80 (15H, m).

IR (KBr): 1645, 1491, 1464, 1258, 1182, 747, 733, 702 cm⁻¹.

(ii) Production of4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-6-methoxy-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) using4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-6-methoxy-N-methyl[1,1′-biphenyl]-3-carboxamide(1.40 g) and pyridine hydrochloride (468 mg), the colorless amorphoustitle compound (576 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.85 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=7.0 Hz),2.58-2.71 (1H, m), 2.96 (3H, d, J=4.4 Hz), 3.83 (3H, s), 6.96-7.00 (3H,m), 7.41-7.54 (5H, m), 7.68 (1H, d, J=2.6 Hz), 7.77 (1H, dd, J=2.6, 8.4Hz).

IR (KBr): 1626, 1603, 1556, 1493, 1262, 1020, 829, 631 cm⁻¹.

Example 51 Production of6-fluoro-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(i) Production of6-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 33-(ii) using3-bromo-4-fluoro-N-methylbenzamide (889 mg), a crude product (2.50 g) of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (3.83 ml) andtetrakis(triphenylphosphine)palladium(0) (221 mg), the colorlessamorphous title compound (1.69 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=7.0 Hz),2.42-2.49 (1H, m), 3.02 (3H, d, J=4.8 Hz), 3.58 (1H, s), 6.13 (1H, brs), 6.78 (1H, d, J=1.4 Hz), 7.11-7.23 (7H, m), 7.31-7.35 (9H, m),7.46-7.72 (7H, m), 7.85 (1H, dd, J=2.4, 7.2 Hz).

IR (KBr): 1647, 1487, 1447, 909, 747, 733, 702 cm⁻¹.

(ii) Production of6-fluoro-4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) using6-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(1.64 g) and pyridine hydrochloride (559 mg), the colorless amorphoustitle compound (535 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=7.0 Hz), 0.99 (3H, d, J=6.0 Hz),2.67 (1H, br s), 2.97 (3H, s), 6.98 (1H, s), 7.17 (1H, dd, J=8.8, 8.8Hz), 7.51-7.57 (5H, m), 7.70-7.73 (1H, m), 7.87 (1H, dd, J=2.6, 7.2 Hz).

IR (KBr): 1645, 1559, 1539, 1487, 1325, 1252, 829 cm⁻¹.

Example 52[4′-[1-hydroxy-(1H-imidazol-4-yl)ethyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(i) Production ofN-methyl-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-carboxamide

To a solution of 3-bromo-N-methylbenzamide (16.0 g) in THF (180 ml) wasslowly added dropwise a solution (1.6 M; 103 ml) of n-butyllithium inhexane at −78° C., and the mixture was stirred at −78° C. for 20 min.Trimethoxyborane (50.2 ml) was added dropwise at −78° C. and the mixturewas stirred at −78° C. for 30 min and at room temperature for 17 h. 2NHydrochloric acid (82.0 ml) was added to the reaction mixture, and afterstirring for 1 h, the reaction mixture was extracted with ethyl acetate,the organic layer was washed with saturated brine and dried. The solventwas evaporated under reduced pressure to give a crude product (22.5 g)of 3-[(methylamino)carbonyl]phenylboronic acid as a pale-yellow oil. Bythe reaction in the same manner as in Example 29-(i) using this product(19.2 g), (4-bromophenyl)(1-trityl-1H-imidazol-4-yl)methanone (10.0 g),2M aqueous sodium carbonate solution (81.2 ml) andtetrakis(triphenylphosphine)palladium(0) (1.17 g), the title compound(6.89 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 3.05 (3H, d, J=4.6 Hz), 6.22 (1H, br s) 7.14-7.22 (6H,m), 7.36-7.55 (10H, m), 7.62-7.78 (6H, m), 8.03 (1H, s), 8.37 (2H, d,J=8.8 Hz).

IR (KBr): 1644, 1526, 1186, 1119, 891, 725, 702 cm⁻¹.

(ii) Production of[4′-(1-hydroxy-(1-trityl-1H-imidazol-4-yl)ethyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 39-(iv) usingN-methyl-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-carboxamide(700 mg) and a solution (1.0 M; 3.83 ml) of methylmagnesium bromide inTHF, the title compound (557 mg) was obtained as colorless powdercrystals.

¹H-NMR (CDCl₃) δ: 1.81 (3H, s), 3.04 (3H, d, J=5.2 Hz), 3.36 (1H, s),6.17 (1H, br s), 6.79 (1H, d, J=1.4 Hz), 7.13-7.18 (6H, m), 7.33-7.51(15H, m), 7.66-7.71 (2H, m). 7.95 (1H, dd, J=1.8, 1.8 Hz).

IR (KBr): 1644, 1547, 1445, 1159, 910, 735, 702 cm⁻¹.

(iii) Production of[4′-[1-hydroxy-(1H-imidazol-4-yl)ethyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 41-(ii) using[4′-[1-hydroxy-(1-trityl-1H-imidazol-4-yl)ethyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(527 mg), 10% palladium carbon (527 mg) and 1N hydrochloric acid (0.935ml), the title compound (144 mg) was obtained as colorless powdercrystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 1.93 (3H, s), 3.00 (3H, s), 6.88 (1H, s),7.44-7.74 (8H, m). 7.99 (1H, s).

IR (KBr): 3279, 1636, 1603, 1582, 1551, 737, 629 cm⁻¹.

Example 53 Production of[4′-[1-hydroxy-(1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(i) Production of[4′-[1-hydroxy-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 39-(iv) usingN-methyl-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-carboxamide(1.50 g) and a solution (3.0 M; 2.74 ml) of ethylmagnesium bromide indiethyl ether, the colorless amorphous title compound (1.34 g) wasobtained.

¹H-NMR (CDCl₃) δ: 0.86 (3H, t, J=7.2 Hz), 2.01-2.24 (2H, m), 3.04 (3H,d, J=2.3 Hz), 3.39 (1H, s), 6.24 (1H, br s), 6.78 (1H, d, J=0.7 Hz),7.13-7.19 (6H, m), 7.31-7.55 (15H, m), 7.67-7.78 (2H, m), 7.94-7.96 (1H,m).

IR (KBr): 1644, 1582, 1541, 1493, 1447, 909, 733,, 700 cm⁻¹.

(ii) Production of[4′-[1-hydroxy-(1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 41-(ii) using[4′-[1-hydroxy-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(1.29 g), 10% palladium carbon (1.29 g)and 1N hydrochloric acid (2.23ml), the colorless amorphous title compound (540 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.90 (3H, t, J=7.6 Hz), 2.22-2.33 (2H, m), 3.00(3H, s), 6.93 (1H, s), 7.43-7.71 (8H, m), 8.00 (1H, s).

IR (KBr): 3189, 1634, 1603, 1582, 1557, 835, 812, 627 cm⁻¹.

Example 54 Production of[4′-[1-hydroxy-(1H-imidazol-4-yl)butyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(i) Production of[4′-[1-hydroxy-(1-trityl-1H-imidazol-4-yl)-3-butenyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 39-(iv) usingN-methyl-[4′-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1′-biphenyl]-3-carboxamide(800 mg) and a solution (1.0 M; 6.57 ml) of allylmagnesium bromide inTHF, the colorless amorphous title compound (770 mg) was obtained.

¹H-NMR (CDCl₃) δ: 2.80-3.05 (5H, m), 3.36 (1H, s), 5.04-5.12 (2H, m),5.66-5.82 (1H, m), 6.23 (1H, br s), 6.79 (1H, d, J=1.4 Hz), 7.12-7.19(6H, m), 7.32-7.54 (15H, m), 7.63-7.78 (2H, m), 7.95-7.96 (1H, m).

IR (KBr): 1644, 1541, 1445, 909, 747, 733, 702 cm⁻¹.

(ii) Production of[4′-[1-hydroxy-(1H-imidazol-4-yl)butyl]-N-methyl[1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 41-(ii) using[4′-[1-hydroxy-(1-trityl-1H-imidazol-4-yl)-3-butenyl]-N-methyl[1,1′-biphenyl]-3-carboxamide(690 mg), 10% palladium carbon (690 mg) and 1N hydrochloric acid (1.17ml), the colorless amorphous title compound (269 mg) was obtained. Thecolorless amorphous title compound (420 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.91 (3H, t, J=7.2 Hz), 1.21-1.43 (2H, m),2.09-2.19 (2H, m), 3.00 (3H, s), 6.91 (1H, s), 7.38-7.58 (6H, m),7.70-7.74 (2H, m), 7.98 (1H, s).

IR (KBr): 3212, 1636, 1582, 1557, 831, 812, 737 cm⁻¹.

Example 55 Production of2-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}-N-methylacetamide(i) Production of 2-(3-bromophenyl)-N-methylacetamide

A mixture of 3-bromophenylacetic acid (3.02 g), a solution (2.0 M; 8.5ml) of methylamine in THF,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.20 g),1-hydroxybenzotriazole (2.60 g) and triethylamine (2.3 ml) was stirredin DMF (30 ml) at room temperature for 24 h. The reaction mixture wasdiluted with ethyl acetate, washed successively with water, 1N aqueoussodium hydroxide solution, 1N hydrochloric acid, aqueous sodium hydrogencarbonate and brine, dried (magnesium sulfate) and concentrated underreduced pressure. The residue was purified by silica gel chomatography(eluent; ethyl acetate). Recrystallization from hexane-ethyl acetategave the title compound (1.30 g) as colorless prism crystals.

¹H-NMR (CDCl₃) δ: 2.70 (3H, d, J=4.8 Hz), 3.45 (2H, s), 5.34 (1H, brs),7.04-7.20 (2H, m), 7.28-7.39 (2H, m).

IR (KBr): 3285, 1651, 1568 cm⁻¹.

(ii) Production of2-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}-N-methylacetamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.47 g), 2-(3-bromophenyl)-N-methylacetamide (0.93 g) andtetrakis(triphenylphosphine)palladium(0) (0.21 g), the title compound(580 mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz),2.36-2.54 (1H, m), 2.76 (3H, d, J=4.6 Hz), 3.55 (1H, s), 3.64 (2H, s),5.41 (1H, brs), 6.78 (1H, d, J=1.4 Hz), 7.08-7.24 (7H, m), 7.28-7.62(17H, m).

IR (KBr): 3303, 2969, 1651, 1481, 1445 cm⁻¹.

(iii) Production of2-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}-N-methylacetamide

By the reaction in the same manner as in Example 4-(iii) using2-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}-N-methylacetamide(1.09 g) and pyridine hydrochloride (309 mg), the title compound (260mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.8 Hz), 0.96 (3H, d, J=6.8 Hz),2.44-2.66 (1H, m), 2.71 (3H, d, J=4.8 Hz), 3.56 (2H, s), 5.88 (1H, brs),6.89 (1H, s), 7.16 (1H, d, J=7.8 Hz), 7.27-7.49 (6H, m), 7.53 (2H, d,J=8.4 Hz).

IR (KBr): 3071, 2969, 1651 cm⁻¹.

Example 56 Production ofN-({4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}methyl)acetamide(i) Production of N-(3-bromobenzyl)acetamide

To a solution of 3-bromobenzylamine hydrochloride (5.20 g) in pyridine(30 ml) was added acetic anhydride (3.2 ml) at 0° C. and the mixture wasstirred at room temperature for 24 h. Water and ethyl acetate were addedto the reaction mixture for partitioning, and the organic layer waswashed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate andbrine, dried (magnesium sulfate) and concentrated under reducedpressure. The residue was recrystallized from hexane-ethyl acetate togive the title compound (4.00 g) as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 2.02 (3H, d, J=1.4 Hz), 4.38 (2H, d, J=6.0 Hz), 6.04(1H, brs), 7.10-7.26 (2H, m), 7.30-7.48 (2H, m).

IR (KBr): 3283, 1636, 1549 cm⁻¹.

(ii) Production ofN-({4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}methyl)acetamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.30 g), N-(3-bromobenzyl)acetamide (1.05 g) andtetrakis(triphenylphosphine)palladium(0) (0.18 g), the title compound(1.24 g) was obtained as a pale-yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.7 Hz), 0.92 (3H, d, J=6.7 Hz), 2.04(3H, s), 2.36-2.54 (1H, m), 3.55 (1H, s), 4.49 (2H, d, J=5.8 Hz), 5.80(1H, brs), 6.78 (1H, d, J=1.4 Hz), 7.06-7.24 (7H, m), 7.26-7.60 (17H,m).

IR (KBr): 3293, 2967, 1659, 1445 cm⁻¹.

(iii) Production ofN-({4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}methyl)acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-({4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}methyl)acetamide(1.05 g) and pyridine hydrochloride (278 mg), the title compound (490mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz), 2.02(3H, s), 2.53-2.70 (1H, m), 4.46 (2H, d, J=5.6 Hz), 5.94 (1H, brs), 6.96(1H, d, J=1.0 Hz), 7.19-7.26 (1H, m), 7.37 (1H, t, J=7.7 Hz), 7.42-7.53(5H, m), 7.58 (2H, d, J=8.4 Hz).

IR (KBr): 3264, 1651, 1559 cm⁻¹.

Example 57 Production of1-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}ethanone(i) Production of1-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}ethanone

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (6.22 g), 3′-bromoacetophenone (2.30 g) andtetrakis(triphenylphosphine)palladium(0) (0.210 g), the title compound(1.50 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=7.0 Hz), 0.93 (3H, d, J=7.0 Hz),2.38-2.58 (1H, m), 2.66 (3H, s), 3.55 (1H, s), 6.78 (1H, d, J=1.4 Hz),7.07-7.20 (6H, m), 7.28-7.40 (9H, m), 7.46-7.71 (6H, m), 7.74-7.84 (1H,m), 7.87-7.95 (1H, m), 8.17 (1H, t, J=1.7 Hz).

IR (KBr): 2967, 1688, 1236 cm⁻¹.

(ii) Production of1-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}ethanone

By the reaction in the same manner as in Example 4-(iii) using1-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}ethanone(3.30 g) and pyridine hydrochloride (870 mg), the title compound (910mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.50-2.80 (4H, m), 6.99 (1H, s), 7.44-7.69 (6H, m), 7.76 (1H, d, J=8.0Hz), 7.90 (1H, d, J=8.0 Hz), 8.15 (1H, s).

IR (KBr): 2971, 1682, 1238 cm⁻¹.

Example 58 Production of(−)-1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

1-(4′-Fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanolobtained in Example 13 was subjected to liquid chromatography (eluent;hexane:ethanol=9:1) using an optically active column (Chiralpak AD) togive(−)-1-(4′-fluoro[1,1′-biphenyl]-3-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanolas an enantiomer of the first eluate.

Optical purity; 99% ee (Chiralpak AD)

[a]_(D) ²⁰−47.1° (C=0.31, methanol)

Example 59 Production of4-fluoro-4′-[1-hydroxy-1-(-1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-carboxamide(i) Production of4-fluoro-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 33-(ii) using5-bromo-2-fluorobenzonitrile (1.04 g), a crude product (3.40 g) of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (5.20 ml) and tetrakis(triphenylphosphine)palladium(0) (211 mg), the title compound (1.25 g)was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=7.0 Hz), 0.93 (3H, d, J=6.6 Hz),2.41-2.48 (1H, m), 3.54 (1H, s), 6.78 (1H, d, J=1.0 Hz), 7.12-7.15 (4H,m), 7.22-7.35 (13H, m), 7.42 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz),7.74-7.81 (2H, m).

IR (KBr): 2236, 1493, 1447, 910, 818, 747, 735, 702 cm⁻¹.

(ii)4-fluoro-4′-[1-hydroxy-1-(-1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-carboxamide

By the reaction in the same manner as in Example 4-(iii) using4-fluoro-4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide(1.20 g) and pyridine hydrochloride (432 mg), the colorless amorphoustitle compound (577 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz),2.57-2.67 (1H, m), 6.98 (1H, s), 7.29 (1H, d, J=6.6 Hz), 7.44 (2H, d,J=8.2 Hz), 7.56-7.63 (3H, m), 7.76-7.79 (2H, m).

IR (KBr): 3133, 2973, 2236, 1493, 1273, 1244, 1119, 1015, 818 cm⁻¹.

Example 60 Production of(−)-N-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide

N-{4′-[1-Hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-[1,1′-biphenyl]-3-ylacetamideobtained in Example 31 was subjected to liquid chromatography (eluent;hexane:ethanol=9:1) using an optically active column (Chiralpak AD) togive(−)-N-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamideas an enantiomer off the first eluate.

Optical purity; 99.9% ee (Chiralpak AD)

[a]_(D) ²⁰−17.3° (C=1.0 methanol)

Example 61 Production of1-(3′,4′-dimethoxy[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(3′,4′-dimethoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 29-(i) using1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.50g), 3,4-dimethoxyphenylboronic acid (762 mg), 2M aqueous sodiumcarbonate solution (2.79 ml) andtetrakis(triphenylphosphine)palladium(0) (96.7 mg), the colorlessamorphous title compound (1.42 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz),2.40-2.53 (1H, m), 3.51 (1H, s), 3.92 (3H, s), 3.95 (3H, s), 6.78 (1H,d, J=1.0 Hz), 6.93 (1H, d, J=8.2 Hz), 7.11-7.16 (8H, m), 7.31-7.35 (10H,m), 7.46 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz).

IR (KBr): 1470, 1445, 1250, 1217, 1173, 747, 731, 702 cm⁻¹.

(ii) Production of1-(3′,4′-dimethoxy[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-(3′,4′-dimethoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.37 g) and pyridine hydrochloride (479 mg), the colorless amorphoustitle compound (660 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=7.0 Hz), 0.99 (3H, d, J=6.6 Hz),2.57-2.67 (1H, m), 3.91 (3H, s), 3.93 (3H, s), 6.90-6.98 (2H, m),7.10-7.15 (2H, m), 7.47-7.63 (5H, m).

IR (KBr): 1526, 1505, 1464, 1219, 1171, 1142, 1026, 829, 806 cm⁻¹.

Example 62 Production of1-(3′-methoxy[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol(i) Production of1-(3′-methoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 29-(i) using1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.50g), 3-methoxyphenylboronic acid (635 mg), 2M aqueous sodium carbonatesolution (2.79 ml) and tetrakis(triphenylphosphine)palladium(0) (96.7mg), the title compound (1.01 g) was obtained as colorless powdercrystals.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=7.0 Hz), 0.93 (3H, d, J=7.0 Hz),2.39-2.49 (1H, m), 3.54 (1H, s), 3.86 (3H, s), 6.77 (1H, d, J=1.4 Hz),6.87 (1H, dd, J=02.4, 7.2 Hz), 7.11-7.19 (8H, m), 7.30-7.38 (10H, m),7.47-7.66 (5H, m).

IR (KBr): 1599, 1480, 1447, 1213, 1167, 909, 822, 747, 733, 702 cm⁻¹.

(ii) Production of1-(3′-methoxy[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol

By the reaction in the same manner as in Example 4-(iii) using1-(3′-methoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(960 mg) and pyridine hydrochloride (354 mg), the colorless amorphoustitle compound (483 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz),2.59-2.69 (1H, m), 3.85 (3H, s), 6.86-6.96 (2H, m), 7.11-7.18 (2H, m),7.29-7.65 (6H, m).

IR (KBr): 1481, 1296, 1219, 1171, 1032, 1015, 826, 775, 696 cm⁻¹.

Example 63 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(4-pyridyl)phenyl]-1-propanol (i)Production of2-methyl-1-[3-(4-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 29-(i) using1-(3-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.20g), 4-pyridylboronic acid (754 mg), 2M aqueous sodium carbonate solution(2.23 ml) and tetrakis(triphenylphosphine)palladium(0) (155 mg), thepale-yellow amorphous title compound (1.13 g) was obtained.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.6 Hz), 0.95 (3H, d, J=6.6 Hz),2.05-2.50 (1H, m), 3.72 (1H, s), 7.86 (1H, d, J=0.6 Hz), 7.10-7.15 (7H,m), 7.27-7.47 (12H, m), 7.51-7.75 (3H, m), 8.62-8.65 (2H, m).

IR (KBr): 1597, 1445, 909, 791, 747, 735, 702, 660 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(4-pyridyl)phenyl]-1-propanol

By the reaction in the same manner as in Example 4-(iii) using2-methyl-1-[3-(4-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.08 g) and pyridine hydrochloride (419 mg), the colorless amorphoustitle compound (477 mg) was obtained.

¹H-NMR (CDCl₃) δ: 0.82 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz),2.59-2.72 (1H, m), 7.00 (1H, s), 7.36-7.62 (6H, m), 7.89 (1H, s),8.57-8.60 (2H, m).

IR (KBr): 3073, 2969, 1599, 1476, 1005, 909, 831, 789, 733, 619 cm⁻¹.

Example 64 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(3-pyridyl)phenyl]-1-propanol (i)Production of2-methyl-1-[3-(3-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 4-(ii) using1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.01 g), diethyl(3-pyridyl)borane (0.497 g) andtetrakis(triphenylphosphine)palladium(0) (0.170 g), the title compound(0.657 g) was obtained as a pale-yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.7 Hz), 0.94 (3H, d, J=6.7 Hz),2.30-2.55 (1H, m), 3.70 (1H, s), 6.78 (1H, d, J=1.4 Hz), 7.05-7.46 (19H,m), 7.50-7.62 (1H, m), 7.69 (1H, s), 7.82 (1H, dt, J=8.0, 2.0 Hz), 8.59(1H, dd, J=2.0, 4.8 Hz), 8.80 (1H, d, J=2.2 Hz).

IR (KBr): 1491, 1470, 1445, 912 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(3-pyridyl)phenyl]-1-propanol

By the reaction in the same manner as in Example 4-(iii) using2-methyl-1-[3-(3-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(0.57 g) and pyridine hydrochloride (208 mg), the title compound (288mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.55-2.76 (1H, m), 6.99 (1H, d, J=1.3 Hz), 7.34-7.47 (3H, m), 7.52 (1H,d, J=1.3 Hz), 7.50-7.59 (1H, m), 7.77 (1H, s), 7.88-7.98 (1H, m), 8.50(1H, dd, J=2.2, 5.0 Hz), 8.75 (1H, dd, J=0.8, 2.2 Hz).

IR (KBr): 2971, 1470, 1022, 970 cm⁻¹.

Example 65 Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(2-pyridyl)phenyl]-1-propanol (i)Production of2-methyl-1-[3-(2-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

1-(3-Bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.15g) and a solution of tri-n-butyl(2-pyridyl)tin (1.01 g) in DMF (10 ml)was deaerated and tetrakis(triphenylphosphine)palladium(0) (73.1 mg) wasadded. The mixture was stirred under an argon atmosphere at 80° C. for 5h and copper(I) iodide (20.1 mg) andtetrakis(triphenylphosphine)palladium(0) (48.7 mg) were added. Themixture was stirred at 100° C. for 18 h. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate, washed with 5%aqueous ethylenediamine solution, water (twice) and saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gelchomatography (eluent; hexane:ethyl acetate=3:1→2:1). Recrystallizationfrom ethyl acetate-hexane gave the title compound (577 mg, 51%) ascolorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz),2.45-2.52 (1H, m), 3.68 (1H, s), 6.86 (1H, d, J=1.6 Hz), 7.10-7.43 (18H,m), 7.58-7.86 (4H, m), 8.09-8.10 (1H, m), 8.66-8.69 (1H, m).

IR (KBr): 1586, 1493, 1472, 1445, 909, 774, 747, 733, 702 cm⁻¹.

(ii) Production of1-(1H-imidazol-4-yl)-2-methyl-1-[3-(2-pyridyl)phenyl]-1-propanol

By the reaction in the same manner as in Example 4-(iii) using2-methyl-1-[3-(2-pyridyl)phenyl]-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(527 mg), pyridine hydrochloride (205 mg), the title compound (197 mg)was obtained as colorless plate crystals.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=7.0 Hz), 0.96 (3H, d, J=6.6 Hz),2.58-2.71 (1H, m), 6.89 (1H, s), 7.17-7.24 (1H, m), 7.35-7.43 (2H, m),7.59 (1H, d, J=7.8 Hz), 7.67-7.79 (3H, m), 8.16 (1H, s), 8.62 (1H, d,J=4.8 Hz).

IR (KBr): 3187, 1584, 1460, 1362, 1304, 1007, 799, 768 cm⁻¹.

Example 66 Production ofN-{3′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide(i) Production ofN-{3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(ii) using1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.02 g), 3-acetamidebenzeneboronic acid (0.531 g) andtetrakis(triphenylphosphine)palladium(0) (0.170 g), the title compound(0.980 g) was obtained as a pale-yellow amorphous powder.

1H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.8 Hz), 0.93 (3H, d, J=6.8 Hz), 2.16(3H, s), 2.35-2.58 (1H, m), 3.68 (1H, brs), 6.80 (1H, d, J=1.4 Hz),7.04-7.18 (6H, m), 7.20-7.42 (13H, m), 7.44-7.56 (3H, m), 7.62-7.74 (2H,m).

IR (KBr): 3289, 1669, 1557, 1493 cm⁻¹.

(ii) Production ofN-{3′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-{3′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}acetamide(0.781 g) and pyridine hydrochloride (290 mg), the title compound (315mg) was obtained as colorless powder crystals.

¹H-NMR (DMSO-d₆) δ: 0.69 (3H, d, J=6.6 Hz), 0.82 (3H, d, J=6.6 Hz), 2.07(3H, s), 2.57-2.78 (1H, m), 5.12 (1H, brs), 6.96 (1H, s), 7.21-7.43 (4H,m), 7.50-7.66 (3H, m), 7.80 (1H, s), 7.88 (1H, s).

IR (KBr): 3295, 1667, 1557, 789 cm⁻¹.

Example 67 Production of5-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-methylnicotinamide(i) Production of 5-bromo-N-methylnicotinamide

By the reaction in the same manner as in Example 55-(i) using5-bromonicotinic acid (5.01 g), a solution (2.0 M ; 30 ml) ofmethylamine in THF, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (5.79 g) and 1-hydroxybenzotriazole (4.72 g), the titlecompound (2.30 g) was obtained as colorless prism crystals.

¹H-NMR (CDCl₃) δ: 3.04 (3H, d, J=4.8 Hz), 6.45 (1H, brs), 8.27 (1H, t,J=2.1 Hz), 8.78 (1H, d, J=2.1 Hz), 8.86 (1H, d, J=2.1 Hz).

IR (KBr): 3297, 3025, 1645, 1416 cm⁻¹.

(ii) Production of5-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methylnicotinamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.0 g), 5-bromo-N-methylnicotinamide (1.01 g) andtetrakis(triphenylphosphine)palladium(0) (0.177 g), the title compound(1.26 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.6 Hz), 0.93 (3H, d, J=6.6 Hz),2.36-2.60 (1H, m), 3.07 (3H, d, J=5.2 Hz), 3.59 (1H, s), 6.30 (1H, brs),6.78 (1H, d, J=1.4 Hz), 7.06-7.20 (6H, m), 7.26-7.38 (10H, m), 7.52 (2H,d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz), 8.29 (1H, t, J=2.2 Hz), 8.88 (1H,d, J=2.2 Hz), 8.94 (1H, d, J=2.2 Hz).

IR (KBr): 3227, 2969, 1651 cm⁻¹.

(iii) Production of5-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-methylnicotinamide

By the reaction in the same manner as in Example 4-(iii) using5-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methylnicotinamide(1.44 g) and pyridine hydrochloride (466 mg), the title compound (360mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.8 Hz), 0.98 (3H, d, J=6.8 Hz),2.40-2.80 (1H, m), 3.02 (3H, s), 6.98 (1H, d, J=1.0 Hz), 7.45 (2H, d,J=8.4 Hz), 7.48 (1H, d, J=1.0 Hz), 7.59 (2H, d, J=8.4 Hz), 8.28 (1H, t,J=2.1 Hz), 8.78 (1H, d, J=2.1 Hz), 8.84 (1H, d, J=2.1 Hz).

IR (KBr): 3200, 2971, 1651, 1557 cm⁻¹.

Example 68 Production ofN-(6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridyl)acetamide(i) Production of N-(6-bromo-2-pyridyl)acetamide

By the reaction in the same manner as in Example 56-(i) using2-amino-6-bromopyridine (2.97 g) and acetic anhydride (2.9 ml), thetitle compound (2.30 g) was obtained as colorless scaly crystals.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 7.21 (1H, d, J=8.0 Hz), 7.56 (1H, t,J=8.0 Hz), 8.05 (1H, brs), 8.15 (1H, d, J=8.0 Hz).

IR (KBr): 3231, 1661, 1574, 1439, 1391 cm⁻¹.

(ii) Production ofN-(6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-2-pyridyl)acetamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.01 g), N-(6-bromo-2-pyridyl)acetamide (1.05 g) andtetrakis(triphenylphosphine)palladium(0) (0.138 g), the title compound(0.720 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.8 Hz) 2.20(3H, s), 2.34-2.58 (1H, m), 3.60 (1H, s), 6.77 (1H, d, J=1.4 Hz),7.06-7.20 (6H, m), 7.28-7.42 (10H, m), 7.44 (1H, dd, J=0.8, 7.9 Hz),7.59 (2H, d, J=8.4 Hz), 7.75 (1H, t, J=7.9 Hz), 7.83 (2H, d, J=8.4 Hz),8.05-8.16 (2H, m).

IR (KBr): 2969, 1732, 1690, 1447 cm⁻¹.

(iii) Production ofN-(6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridyl)acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-(6-(4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-2-pyridyl)acetamide(1.48 g) and pyridine hydrochloride (520 mg), the title compound (520mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz),2.22 (3H, s), 2.52-2.74 (1H, m), 6.97 (1H, d, J=1.0 Hz), 7.44 (1H, d,J=7.8 Hz), 7.52 (1H, d, J=1.0 Hz), 7.59 (2H, d, J=8.4 Hz), 7.76 (1H, t,J=7.8 Hz), 7.83 (2H, d, J=8.4 Hz), 8.09 (1H, d, J=7.8 Hz).

IR (KBr): 3177, 2967, 1651, 1559, 1451 cm⁻¹.

Example 69 Production of6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-methyl-2-pyridinecarboxamide(i) Production of 6-bromo-N-methyl-2-pyridinecarboxamide

By the reaction in the same manner as in Example 55-(i) using6-bromopicolinic acid (3.00 g), a solution (2.0 M; 18 ml) of methylaminein THF, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(3.41 g) and 1-hydroxybenzotriazole (2.99 g), the title compound (2.60g) was obtained as pale-brown oil.

¹H-NMR (CDCl₃) δ: 3.04 (3H, d, J=5.2 Hz), 7.60 (1H, dd, J=1.0, 7.6 Hz),7.72 (1H, t, J=7.6 Hz), 8.16 (1H, dd, J=1.0, 7.6 Hz).

IR (neat): 3391, 1682, 1669, 1557, 1539 cm⁻¹.

(ii) Production of6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methyl-2-pyridinecarboxamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (2.97 g), 6-bromo-N-methyl-2-pyridinecarboxamide (1.30 g) andtetrakis(triphenylphosphine)palladium(0) (0.110 g), the title compound(1.11 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.76 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz),2.44-2.64 (1H, m), 3.04-3.10 (3H, m), 6.83 (1H, d, J=1.2 Hz), 7.08-7.20(6H, m), 7.30-7.40 (10H, m), 7.63 (2H, d, J=8.4 Hz), 7.82-7.98 (4H, m),8.06-8.14 (1H, m), 8.33 (1H, brs).

IR (KBr): 3387, 2967, 1672, 1449 cm⁻¹.

(iii) Production of6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-methyl-2-pyridinecarboxamide

By the reaction in the same manner as in Example 4-(iii) using6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methyl-2-pyridinecarboxamide(1.44 g) and pyridine hydrochloride (550 mg), the title compound (255mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.81 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.48-2.70 (1H, m), 3.02 (3H, d, J=5.2 Hz), 6.98 (1H, s), 7.48 (1H, s),7.64 (2H, d, J=8.4 Hz), 7.70-7.83 (2H, m), 7.88 (2H, d, J=8.4 Hz), 8.04(1H, d, J=7.0 Hz), 8.16-8.30 (1H, m).

IR (KBr): 2969, 1667, 1537, 1449 cm⁻¹.

Example 70 Production ofN-(2-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-4-pyridyl)acetamide(i) Production of1-[4-(4-amino-2-pyridyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (5.78 g), 4-amino-2-chloropyridine (1.00 g), sodium bromide (810mg) and tetrakis(triphenylphosphine)palladium(0) (0.190 g), the titlecompound (2.30 g) was obtained as a yellow amorphous powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.5 Hz), 0.91 (3H, d, J=6.5 Hz),2.36-2.56 (1H, m), 3.61 (1H, s), 4.17 (2H, s), 6.46 (1H, dd, J=2.2, 5.6Hz), 6.77 (1H, s), 6.93 (1H, d, J=2.2 Hz), 7.06-7.19 (6H, m), 7.27-7.39(10H, m), 7.56 (2H, d, J=8.2 Hz), 7.82 (2H, d, J=8.2 Hz), 8.29 (1H, d,J=5.6 Hz).

IR (KBr): 3335, 3210, 1599, 1445 cm⁻¹.

(ii) Production ofN-(2-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-4-pyridyl)acetamide

A mixture of1-[4-(4-amino-2-pyridyl)phenyl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(1.40 g), acetic anhydride (0.46 ml), triethylamine (0.71 ml) andp-dimethylaminopyridine (20 mg) was stirred in THF (20 ml) at 60° C. for16 h. The solvent was evaporated and ethyl acetate and water were addedto the residue for partitioning. The organic layer was washed withaqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate)and concentrated under reduced pressure. The residue was dissolved in amixture of acetonitrile (10 ml)—water (10 ml) and tetrabutylammoniumbromide (13 mg) was added. The mixture was stirred at room temperaturefor 10 h. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The organic layer was combined, and themixture was dried (magnesium sulfate) and concentrated under reducedpressure. The residue was purified by silica gel chomatography (eluent;hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate gave thetitle compound (630 mg) as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.74 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=6.8 Hz),2.19 (3H, s), 2.42-2.62 (1H, m), 6.82 (1H, d, J=1.0 Hz), 7.06-7.20 (6H,m), 7.26-7.42 (10H, m), 7.50-7.62 (3H, m), 7.77-7.88 (3H, m), 8.46 (1H,d, J=5.6 Hz).

IR (KBr): 3264, 2973, 1707, 1588 cm⁻¹.

(iii) Production ofN-(2-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-4-pyridyl)acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-(2-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-4-pyridyl)acetamide(0.590 g) and pyridine hydrochloride (190 mg), the title compound (150mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.81 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.19 (3H, s), 2.50-2.78 (1H, m), 6.98 (1H, m), 7.50-7.66 (4H, m),7.74-7.86 (2H, m), 7.92 (1H, s), 8.43 (1H, dd, J=2.6, 7.4 Hz).

IR (KBr): 3094, 1703, 1599, 1522 cm⁻¹.

Example 71 Production ofN-ethyl-6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridinecarboxamide(i) Production of 6-bromo-N-ethyl-2-pyridinecarboxamide

By the reaction in the same manner as in Example 55-(i) using6-bromopicolinic acid (3.06 g), ethylamine hydrochloride (2.49 g),triethylamine (6 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (3.61 g) and 1-hydroxybenzotriazole (2.66 g), the titlecompound (3.20 g) was obtained as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.3 Hz), 3.40-3.64 (2H, m), 7.60 (1H,d, J=7.9 Hz), 7.72 (1H, t, J=7.9 Hz), 7.82 (1H, brs), 8.16 (1H, d, J=7.9Hz).

IR (KBr): 2975, 1669, 1557, 1532, 1427 cm⁻¹.

(ii) Production ofN-ethyl-6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-2-pyridinecarboxamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.10 g), 6-bromo-N-ethyl-2-pyridinecarboxamide (1.20 g) andtetrakis(triphenylphosphine)palladium(0) (0.170 g), the title compound(1.89 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=7.0 Hz), 0.93 (3H, d, J=7.0 Hz), 1.31(3H, t, J=7.3 Hz), 2.40-2.60 (1H, m), 3.44-3.64 (2H, m), 3.54 (1H, s),6.79 (1H, d, J=1.6 Hz), 7.08-7.19 (6H, m), 7.28-7.39 (10H, m), 7.66 (2H,d, J=8.8 Hz), 7.79-7.96 (4H, m), 8.13 (1H, dd, J=1.4, 7.4 Hz).

IR (KBr): 1671, 1524, 1449 cm⁻¹.

(iii) Production ofN-ethyl-6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridinecarboxamide

By the reaction in the same manner as in Example 4-(iii) usingN-ethyl-6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-2-pyridinecarboxamide(1.82 g) and pyridine hydrochloride (570 mg), the title compound (560mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.84 (3H, d, J=6.6 Hz), 1.00 (3H, d, J=6.6 Hz), 1.29(3H, t, J=7.3 Hz), 2.56-2.78 (1H, m), 3.44-3.64 (2H, m), 7.01 (1H, d,J=1.2 Hz), 7.55 (1H, d, J=1.2 Hz), 7.69 (2H, d, J=8.6 Hz), 7.77-7.88(2H, m), 7.93 (2H, d, J=8.6 Hz), 8.10 (1H, dd, J=1.4, 7.0 Hz), 8.18 (1H,brs).

IR (KBr): 3441, 3395, 2975, 1676, 1530, 1449 cm⁻¹.

Example 72 Production of6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-isopropyl-2-pyridinecarboxamide(i) Production of 6-bromo-N-isopropyl-2-pyridinecarboxamide

By the reaction in the same manner as in Example 55-(i) using6-bromopicolinic acid (3.04 g), isopropylamine (5 ml),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.44 g)and 1-hydroxybenzotriazole (2.70 g), the title compound (3.10 g) wasobtained as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=6.6 Hz), 4.10-4.40 (1H, m), 7.60 (1H,dd, J=1.2, 7.8 Hz), 7.71 (1H, t, J=7.8 Hz), 8.16 (1H, dd, J=1.2, 7.8Hz).

IR (KBr): 2973, 1674, 1557, 1520 cm⁻¹.

(ii) Production of6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-isopropyl-2-pyridinecarboxamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (3.10 g), 6-bromo-N-isopropyl-2-pyridinecarboxamide (1.13 g) andtetrakis(triphenylphosphine)palladium(0) (0.160 g), the title compound(1.67 g) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.78 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz), 1.32(6H, d, J=6.6 Hz), 2.40-2.58 (1H, m), 3.56 (1H, s), 4.20-4.42 (1H, m),6.80 (1H, s), 7.00-7.20 (6H, m), 7.21-7.46 (10H, m), 7.66 (2H, d, J=8.5Hz), 7.79-7.86 (1H, m), 7.92 (2H, d, J=8.5 Hz), 8.04 (1H, d, J=7.4 Hz),8.14 (1H, dd, J=1.0, 6.2 Hz).

IR (KBr): 3382, 2969, 1667, 1524, 1447 cm⁻¹.

(iii) Production of6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-isopropyl-2-pyridinecarboxamide

By the reaction in the same manner as in Example 4-(iii) using6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-isopropyl-2-pyridinecarboxamide(1.60 g) and pyridine hydrochloride (770 mg), the title compound (350mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.80 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz), 1.25(6H, d, J=6.6 Hz), 2.44-2.70 (2H, m), 6.93 (1H, d, J=0.9 Hz), 7.41 (1H,d, J=7.8 Hz), 7.46 (1H, d, J=0.9 Hz), 7.60 (2H, d, J=8.4 Hz), 7.73 (1H,t, J=7.8 Hz), 7.84 (2H, d, J=8.4 Hz), 8.15 (1H, d, J=7.8 Hz), 8.15 (1H,brs).

IR (KBr): 2973, 1672, 1518,1447 cm⁻¹.

Example 73 Production of2-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-methylisonicotinamide(i) Production of 2-bromo-N-methylisonicotinamide

By the reaction in the same manner as in Example 55-(i) using2-bromoisonicotinic acid (2.69 g), a solution (2.0 M; 15 ml) ofmethylamine in THF, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (3.20 g) and 1-hydroxybenzotriazole (2.59 g), the titlecompound (361 mg) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 3.04 (3H, d, J=4.6 Hz), 7.55 (1H, dd, J=1.4, 5.1 Hz),7.79-7.82 (1H, m), 8.49 (1H, d, J=5.1 Hz).

IR (KBr): 3291, 1644, 1557, 1537 cm⁻¹.

(ii) Production of2-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methylisonicotinamide

By the reaction in the same manner as in Example 33-(ii) using4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid (1.30 g), 2-bromo-N-methylisonicotinamide (310 mg) andtetrakis(triphenylphosphine)palladium(0) (0.110 g), the title compound(480 mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz),2.36-2.54 (1H, m), 3.06 (3H, d, J=4.8 Hz), 3.61 (1H, s), 6.36 (1H, brs),6.78 (1H, d, J=1.4 Hz), 7.06-7.18 (6H, m), 7.28-7.38 (10H, m), 7.45 (1H,dd, J=1.4, 5.2 Hz), 7.61 (2H, d, J=8.4 Hz), 7.93 (2H, d, J=8.4 Hz),8.05-8.20 (1H, m), 8.75 (1H, dd, J=0.6, 5.2 Hz).

IR (KBr): 3304, 1651, 1549 cm⁻¹.

(iii) Production of2-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-N-methylisonicotinamide

By the reaction in the same manner as in Example 4-(iii) using2-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methylisonicotinamide(0.450 g) and pyridine hydrochloride (230 mg), the title compound (110mg) was obtained as a colorless amorphous powder.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.79 (3H, d, J=6.6 Hz), 0.98 (3H, d, J=6.6 Hz),2.52-2.76 (1H, m), 3.02 (3H, s), 6.95 (1H, d, J=1.0 Hz), 7.44-7.60 (4H,m), 7.81 (2H, d, J=8.4 Hz), 7.97 (1H, s), 8.67 (1H, d, J=5.2 Hz).

IR (KBr): 3175, 2973, 1651, 1549 cm⁻¹.

Example 74 Production ofN-[4′-fluoro-5-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-2-yl]acetamide(i) Production of 4′-fluoro[1,1′-biphenyl]-2-yl methyl ether

By the reaction in the same manner as in Example 4-(ii) using2-bromoanisole (8.91 g), 4-fluorophenylboronic acid (10.0 g), 2M aqueoussodium carbonate solution (47.6 ml) andtetrakis(triphenylphosphine)palladium(0) (2.20 g), the title compound(8.14 g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 3.81 (3H, s), 6.96-7.13 (4H, m), 7.27-7.37 (2H, m),7.45-7.33 (2H, m).

IR (KBr): 1514, 1487, 1260, 1236, 1223, 1159, 1028, 835, 754 cm⁻¹.

(ii) Production of 5-bromo-4′-fluoro[1,1′-biphenyl]-2-ol

A mixture of 4′-fluoro[1,1′-biphenyl]-2-yl methyl ether (107 g),pyridinium hydrobromide perbromide (34.0 g) and water-aceticacid-diethyl ether mixed solution (1:4:5, 500 ml) was stirred for 18 hat room temperature. Hypowater was added to the reaction mixture and themixture was concentrated. The resulting crystals were collected byfiltration to give a crude product (15.2 g) of5-bromo-4′-fluoro[1,1′-biphenyl]-2-yl methyl ether as a yellow solid. Toa solution of this product (14.1 g) in dichloromethane (150 ml) wasadded dropwise a solution of boron tribromide (5.69 ml) indichloromethane (40 ml) at −78° C., and the mixture was stirred at roomtemperature ifor 18 h. The reaction mixture was poured into ice and theorganic layer was separated, neutralized with aqueous sodium hydrogencarbonate, washed with brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel chomatography (eluent;hexane→hexane:ethylacetate=5:1) to give the title compound (13.2 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 5.11 (1H, s), 6.83-6.86 (1H, m), 7.13-7.24 (2H, m),7.32-7.46 (4H, m).

IR (KBr): 1514, 1487, 1480, 1260, 1229, 1159, 839, 812 cm⁻¹.

(iii) Production of4′-fluoro-5-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-ol

To a solution of 5-bromo-4′-fluoro[1,1′-biphenyl]-2-ol (13.2 g) andimidazole (5.04 g) in DMF (60 ml) was added at 0° C.t-butyldimethylsilyl chloride (7.82 g), and the mixture was stirred atroom temperature for 21 h. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate, washed twice with waterand with brine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give a crude product (18.1 g) of3-bromo-6-[[tert-butyl(dimethyl)silyl]oxy]-4′-fluoro-1,1′-biphenyl as ayellow oil. By the reaction in the same manner as in Example 4-(i) usingthis product (18.1 g), a solution (1.6 M; 31.3 ml) of n-butyllithium inhexane and 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propane (12.0 g), acolorless amorphous and crude product (18.2 g) of1-[4′-fluoro-6-[[tert-butyl(dimethyl)silyl]oxy][1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanolwas obtained. To a solution of this product (18.2 g) in THF (100 ml) wasadded dropwise a solution (1.0 M; 27.7 ml) of tetrabutylammonium bromidein THF at 0° C., and the mixture was stirred at room temperature for 15h. Water and ethyl acetate were added to the reaction mixture and themixture was concentrated. Ethyl acetate and diisopropyl ether were addedto the residue and the precipitated crystals were collected byfiltration, washed with diisopropyl ether and dried under reducedpressure to give the title compound (11.2 g) as a colorless powder.

¹H-NMR (DMSO-d₆) δ: 0.65 (3H, d, J=6.6 Hz), 0.73 (3H, d, J=6.6 Hz),2.44-2.51 (1H, m), 4.92 (1H, s), 6.78-6.83 (2H, m), 7.04-7.08 (7H, m),7.16-7.55 (15H, m), 9.37 (1H, s).

IR (KBr): 1501, 1271, 1223, 1184, 1157, 1001, 835, 756, 748, 702 cm⁻¹.

(iv) Production of4′-fluoro-5-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-yltrifluoromethanesulfonate

To a solution of4′-fluoro-5-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-ol(1.10 g) in pyridine (7 ml) was added dropwise at 0° C.trifluoromethanesulfonic anhydride (0.423 ml), and the mixture wasstirred at 0° C. for 20 min and at room temperature for 40 min. Thereaction mixture was concentrated under reduced pressure, diluted withethyl acetate. The mixture was washed 3 times with 5% aqueous citricacid solution, and with water, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel chomatography (eluent;hexane:ethylacetate=5:1) to give the colorless amorphous title compound (1.06 g).

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.6 Hz), 0.92 (3H, d, J=6.6 Hz),2.35-2.42 (1H, m), 3.74 (1H, s), 6.74 (1H, d, J=1.6 Hz), 7.08-7.17 (7H,m), 7.24-7.40 (14H, m), 7.52-7.61 (2H, m).

IR (KBr): 1481, 1424, 1248, 1217, 1161, 1140, 885, 837, 747, 702 cm⁻¹.

(v) Production of1-[6-[(diphenylmethylene)amino]-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

To a solution of4′-fluoro-5-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-yltrifluoromethanesulfonate (1.06 g), benzophenone imine (0.035 ml) andcecium carbonate (1.23 g) in toluene (15 ml) were added(RS)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56.4 mg) andtri(dibenzylideneacetone)dipalladium(0) (27.7 mg), and the mixture wasstirred at 80-90° C. for 26 h.(RS)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (112 mg) andtri(dibenzylideneacetone)palladium(0) (55.4 mg) were further added, andthe mixture was stirred at 80-90° C. for 16.5 h, and at 105° C. for 3.5h. The reaction mixture was filtered through Celite, and the filtratewas washed with water and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel chomatography (eluent;hexane:ethyl acetate=5:1→1:1) to give the yellow amorphous titlecompound (115 mg).

¹H-NMR (CDCl₃) δ: 0.69 (3H, d, J=6.6 Hz), 0.88 (3H, d, J=7.0 Hz),2.28-2.35 (1H, m), 3.60 (1H, s), 6.60-6.66 (3H, m), 6.82-7.44 (29H, m),7.60-7.64 (2H, m).

IR (KBr): 1599, 1510, 1491, 1480, 1447, 1223, 1157, 909, 837, 747, 735,700 cm⁻¹.

(vi) Production ofN-[4′-fluoro-5-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-yl]acetamide

To a solution of1-[6-[(diphenylmethylene)amino]-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(110 mg) in THF-methanol (1:1) (6 ml) were added anhydrous sodiumacetate (29.6 mg) and hydroxyammonium chloride (18.7 mg) at roomtemperature, and the mixture was stirred for 22 h. The reaction mixturewas concentrated, diluted with ethyl acetate, washed with 0.5N aqueoussodium hydroxide solution and saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive a crude product (118 mg) of1-[6-amino-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanolas a yellow oil. To a solution of this product (116 mg) and pyridine(29.6 μl) in THF (2 ml) was added dropwise acetic anhydride (28.3 μl) at0° C., and the mixture was stirred at room temperature for 16 h.Saturated aqueous sodium hydrogen carbonate was added to the reactionmixture and the mixture was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel chomatography(eluent; hexane:ethyl acetate=3:1→3:2) to give the colorless amorphoustitle compound (79.6 mg).

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.6 Hz), 0.91 (3H, d, J=6.6 Hz), 2.02(3H, s), 2.30-2.41 (1H, m), 3.64 (1H, s), 6.73 (1H, d, J=1.6 Hz), 6.96(1H, br s), 7.09-7.19 (8H, m), 7.29-7.39 (14H, m), 8.09 (1H, d, J=8.8Hz).

IR (KBr): 1669, 1514, 1493, 1472, 1447, 1225, 1159, 747, 733, 702 cm⁻¹.

(vii) Production ofN-[4′-fluoro-5-[1-hydroxy-1-(1H-imidazole-4-imidazole)-2-methylpropyl][1,1′-biphenyl]-2-yl]acetamide

By the reaction in the same manner as in Example 4-(iii) usingN-[4′-fluoro-5-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-yl]acetamide(78.2 mg) and pyridine hydrochloride (26.7 mg), the title compound (25.0mg) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.83 (3H, d, J=6.8 Hz), 0.95 (3H, d, J=6.6 Hz), 2.02(3H, s), 2.52-2.66 (1H, m), 6.95 (1H, br s) 7.10-7.19 (1H, m), 7.29-7.36(3H, m), 7.47-7.52 (3H, m), 8.11 (1H, d, J=8.8 Hz).

IR (KBr): 3169, 2973, 1665, 1514, 1491, 1304, 1225, 839, 820 cm⁻¹.

Example 75 Production of4′-fluoro-5-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-2-ylacetate (i) Production of benzyl 5-bromo-4′-fluoro[1,1′-biphenyl]-2-ylether

A solution of 5-bromo-4′-fluoro[1,1′-biphenyl]-2-ol (7.00 g), potassiumcarbonate (3.80 g) and benzyl bromide (3.27 ml) in DMF (10 ml) wasstirred at 60° C. for 5 h. The reaction mixture was diluted with water,extracted with ethyl acetate, washed with water and saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gelchomatography (eluent; hexane→hexane:ethyl acetate=10:1) to give thetitle compound (8.31 g) as a brown oil.

¹H-NMR (CD₃OD) δ: 5.05 (2H, s), 6.89 (1H, d, J=8.8 Hz), 7.04-7.14 (2H,m), 7.25-7.55 (9H, m).

IR (KBr): 1512, 1483, 1454, 1265, 1227, 1159, 1024, 837, 737 cm⁻¹.

(ii) Production of1-[6-benzyloxy-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol

By the reaction in the same manner as in Example 4-(i) using benzyl5-bromo-4′-fluoro[1,1′-biphenyl]-2-yl ether (3.86 g), a solution (1.6 M;7.29 ml) of n-butyllithium in hexane and1-(1H-imidazol-4-yl)-2-methyl-1-propane (597 mg), the colorlessamorphous title compound (672 mg) was obtained.

¹H-NMR (CDCl₃) δ: 0.84 (3H, d, J=7.0 Hz), 0.96 (3H, d, J=6.6 Hz),2.53-2.67 (1H, m), 5.05 (2H, s), 6.94-7.10 (4H, m), 7.30-7.33 (5H, m),7.43-7.56 (5H, m).

IR (KBr): 1514, 1491, 1265, 1225, 1157, 1017, 837, 735 cm⁻¹.

(iii) Production of4′-fluoro-5-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-2-ol

A suspension of1-[6-benzyloxy-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol(647 mg) and 10% palladium carbon (647 mg) in methanol (15 ml) wasstirred under a hydrogen atmosphere at room temperature for 4 h. Thereaction mixture was filtered through Celite and the filtrate wasconcentrated. The residue was purified by silica gel chomatography(eluent; ethyl acetate→ethyl acetate:methanol=20:1). Recrystallizationfrom ethyl acetate-hexane gave the title compound (396 mg) as colorlesspowder crystals.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=7.0 Hz), 0.95 (3H, d, J=7.0 Hz),2.52-2.65 (1H, m), 6.65 (1H, d, J=8.4 Hz), 6.94 (1H, d, J=1.2 Hz),7.04-7.14 (2H, m), 7.26 (1H, d, J=2.2, 8.4 Hz), 7.34 (1H, d, J=2.2 Hz),7.47-7.54 (3H, m).

IR (KBr): 1514, 1493, 1229, 1213, 1007, 841, 814, 627, 606 cm⁻¹.

(iv) Production of4′-fluoro-5-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-2-ylacetate

To a solution of4′-fluoro-5-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-2-ol(390 mg) in pyridine (4 ml) was added dropwise acetic anhydride (0.135ml) at room temperature, and the mixture was stirred for 4 h. Aceticanhydride (22.5 μl) was further added and the mixture was stirred for 15h. The reaction mixture was subjected to azeotropic reaction withtoluene for concentration, diluted with ethyl acetate, washed with waterand saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and to a solution of theresidue (414 mg) in pyridine (4 ml) was added dropwise acetic anhydride(0.209 ml) at room temperature. The mixture was stirred for 15 h and thereaction mixture was subjected to azeotropic reaction with toluene forconcentration. To a solution of the residue in methanol (15 ml) wasadded 0.1N aqueous p-toluenesulfonic acid solution (7.5 ml) at roomtemperature, and the mixture was stirred for 1 h. The reaction mixturewas concentrated, diluted with ethyl acetate, neutralized with saturatedaqueous sodium hydrogen carbonate, extracted with ethyl acetate, washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by column chomatography (eluent; ethyl acetate→ethylacetate:methanol=20:1) to give the colorless amorphous title compound(337 mg).

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=6.6 Hz), 0.96 (3H, d, J=6.6 Hz),2.08 (3H, s), 2.57-2.65 (1H, m), 6.96 (1H, d, J=1.0 Hz), 7.03-7.11 (3H,m), 7.32-7.39 (2H, m), 7.50-7.59 (3H, m).

IR (KBr): 1748, 1516, 1487, 1372, 1223, 1196, 1161, 839 cm⁻¹.

Example 76 Production of5-[4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl]-N-methyl-2-thiophenecarboxamide(i) Production of5-[4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl]-N-methyl-2-thiophenecarboxamide

By the reaction in the same manner as in Example 33-(ii) using5-bromo-N-methyl-2-thiophenecarboxamide (1.01 g), a crude product (3.00g) of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (4.59 ml) andtetrakis(triphenylphosphine)palladium(0) (265 mg), the title compound(1.44 g) was obtained as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 0.75 (3H, d, J=6.8 Hz), 0.92 (3H, d, J=7.0 Hz),2.43-2.47 (1H, m), 3.01 (3H, d, J=4.8 Hz), 3.53 (1H, s), 5.93 (1H, brs), 6.76 (1H, d, J=1.4 Hz), 7.10-7.15 (7H, m), 7.24-7.53 (15H, m).

IR (KBr): 1626, 1553, 1493, 1449, 810, 747, 733, 702 cm⁻¹.

(ii) Production of5-[4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl]-N-methyl-2-thiophenecarboxamide

By the reaction in the same manner as in Example 4-(iii) using5-[4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl]-N-methyl-2-thiophenecarboxamide(1.39 g) and pyridine hydrochloride (484 mg), the colorless amorphoustitle compound (769 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.82 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=7.0 Hz),2.59-2.66 (1H, m), 2.97 (3H, s), 6.96 (1H, d, J=0.8 Hz), 7.22 (1H, d,J=4.0 Hz), 7.47 (1H, d, J=4.0 Hz), 7.54-7.56 (5H, m).

IR (KBr): 3079, 1626, 1557, 1528, 1451, 1410, 1314, 812 cm⁻¹.

Example 77 Production of5-[4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl]-N-methyl-2-thiophenesulfonamide(i) Production of5-[4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl]-N-methyl-2-thiophenesulfonamide

By the reaction in the same manner as in Example 33-(ii) using5-bromo-N-methyl-2-thiophenesulfonamide (1.18 g), a crude product (3.00g) of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (4.59 ml) andtetrakis(triphenylphosphine)palladium(0) (265 mg), the title compound(1.67 g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.74 (3H, d, J=7.0 Hz), 0.92 (3H, d, J=6.6 Hz),2.40-2.47 (1H, m), 2.78 (3H, d, J=5.6 Hz), 3.54 (1H, s), 4.44 (1H, qJ=5.6 Hz), 6.76 (1H, d, J=1.2 Hz), 7.10-7.15 (6H, m), 7.22-7.35 (11H,m), 7.48-7.58 (5H, m).

IR (KBr): 1445, 1335, 1159, 808, 747, 733, 702, 594 cm⁻¹.

(ii) Production of5-[4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl]-N-methyl-2-thiophenesulfonamide

By the reaction in the same manner as in Example 4-(iii) using5-[4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyliphenyl]-N-methyl-2-thiophenesulfonamide(1.62 g) and pyridine hydrochloride (532 mg), the colorless amorphoustitle compound (884 mg) was obtained.

¹H-NMR (CDCl₃+CD₃OD) δ: 0.80 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.6 Hz),2.56-2.72 (4H, m), 6.97 (1H, s), 7.21 (1H, d, J=4.0 Hz), 7.30 (1H, s),7.48-7.58 (5H, m).

IR (KBr): 1435, 1327, 1157, 1134, 1090, 1015, 806, 594 cm⁻¹.

Example 78 Production of4-[4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl]]-1-isoindolinone(i) Production of methyl 3-bromo-2-methylbenzoate

A solution of 3-bromo-2-methylbenzoic acid (9.95 g) and conc. sulfuricacid (0.2 ml) in methanol (50 ml) was stirred at room temperature for 69h and heated under reflux for 96 h. The reaction mixture was neutralizedwith 1N aqueous sodium hydroxide solution and concentrated. The residuewas diluted with ethyl acetate, washed 3 times with 1N aqueous sodiumhydroxide solution and with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure togive the title compound (10.2 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 2.65 (3H, s), 3.93 (3H, s), 7.12 (1H, dd, J=8.0, 8.0Hz), 7.69-7.77 (2H, m).

IR (KBr): 1728, 1435, 1285, 1256, 1215, 1098, 754 cm⁻¹.

(ii) Production of methyl 3-bromo-2-(bromomethyl)benzoate

A solution of methyl 3-bromo-2-methylbenzoate (1.00 g),N-bromosuccinimide (855 mg) and 2,2′-azobis(isobutyronitrile) (71.8 mg)in carbon tetrachloride (50 ml) was heated under reflux for 8 h. Thereaction mixture was concentrated, and the residue was diluted withethyl acetate, washed with saturated aqueous sodium hydrogen carbonateand saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by column chomatography (eluent; hexane:ethyl acetate=20:1) togive the title compound (1.29 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 3.96 (3H, s), 5.14 (2H, s), 7.23 (1H, dd, J=6.8, 6.8Hz), 7.77 (1H, dd, J=1.2, 6.8 Hz), 7.89 (1H, dd, J=1.2, 6.8 Hz).

IR (KBr): 1725, 1435, 1291, 1264, 1223, 1115, 760 cm⁻¹.

(iii) Production of 4-bromo-1-isoindolinone

Methyl 3-bromo-2-(bromomethyl)benzoate (1.28 g) was dissolved in a 11%solution of ammonia in methanol-THF mixed solution (3:2, 25 ml) and themixture was stirred at room temperature for 16 h. The reaction mixturewas concentrated and the residue was washed with saturated brine.Recrystallization from ethyl acetate-hexane gave the title compound (671mg, 76%) as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 4.42 (2H, s), 7.42 (1H, dd, J=7.8, 7.8 Hz), 7.48 (1H,br s), 7.73 (1H, d, J=7.8 Hz), 7.85 (1H, d, J=7.8 Hz).

IR (KBr): 3167, 1728, 1684, 1667, 1470, 1462, 1107, 745 cm⁻¹.

(iv) Production of4-[4-[1-hydroxy-2-methyl1-(1-trityl-1H-imidazol-4-yl)-propyl]phenyl]]-1-isoindolinone

By the reaction in the same manner as in Example 33-(ii) using4-bromo-1-isoindolinone (620 mg), a crude product (2.06 g) of4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronicacid, 2M aqueous sodium carbonate solution (2.92 ml) andtetrakis(triphenylphosphine)palladium(0) (169 mg), the title compound(1.07 g) was obtained as colorless needle crystals.

¹H-NMR (CDCl₃) δ: 0.77 (3H, d, J=6.6 Hz), 0.94 (3H, d, J=6.6 Hz),2.42-2.49 (1H, m), 3.60 (1H, s), 4.51 (2H, s), 6.38 (1H, br s), 6.79(1H, d, J=1.0 Hz), 7.11-7.16 (6H, m), 7.32-7.39 (12H, m), 7.55-7.62 (4H,m), 7.85 (1H, dd, J=2.2, 6.2 Hz).

IR (KBr): 1694, 1491, 1478, 1445, 812, 756, 702 cm⁻¹.

(v) Production of4-[4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl]]-1-isoindolinone

A solution of4-[4-[1-hydroxy-2-methyl1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl]]-1-isoindolinone(1.02 g) in 90% formic acid-THF(1:1, 8 ml) was heated under reflux for1.5 h. The reaction mixture was concentrated, and the residue wasdiluted with THF-ethyl acetate mixture (1:1), washed with saturatedaqueous sodium hydrogen carbonate-saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by column chomatography (eluent;dichloromethane→dichloromethane:methanol=20:1→7:1) to give the colorlessamorphous title compound (503 mg).

¹H-NMR (CDCl₃+CD₃OD) δ: 0.83 (3H, d, J=6.6 Hz), 0.99 (3H, d, J=6.6 Hz),2.58-2.72 (1H, m), 4.46 (2H, s), 7.01 (1H, d, J=1.2 Hz), 7.37 (2H, d,J=8.4 Hz), 7.50-7.57 (3H, m), 7.62 (2H, d, J=8.6 Hz), 7.84 (1H, dd,J=2.2, 6.2 Hz).

IR (KBr): 1682, 1480, 1456, 862, 812, 756, 741 cm⁻¹.

Example 79 Production of(−)-N-(6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridyl)acetamide

N-(6-{4-[1-Hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridyl)acetamideobtained in Example 68 was subjected to liquid chromatography (eluent;hexane:ethanol=9:1) using an optically active column (Chiralpak AD) togive(−)-N-(6-{4-(1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridyl)acetamideas an enantiomer of the first eluate.

Optical purity; >99.9% ee (Chiralpak AD)

[a]_(D) ²⁰−11.8° (C=1.02, methanol)

Formulation Example 1

Capsules

(1) Compound obtained in Example 6 10 mg (2) lactose 90 mg (3)microcrystalline cellulose 70 mg (4) magnesium stearate 10 mg

One Capsule 180 mg

The entire amount of the above (1), (2) and (3) and 5 mg of (4) wereadmixed. The mixture was granulated and the remaining 5 mg of (4) wasadded. The whole content was sealed in a gelation capsule.

Formulation Example 2

Tablets

(1) Compound obtained in Example 9  10 mg (2) lactose  35 mg (3) cornstarch 150 mg (4) microcrystalline cellulose  30 mg (5) magnesiumstearate  5 mg One Tablet 230 mg

The entire amount of above (1), (2) and (3), 20 mg of (4) and 2.5 mg of(5) were admixed. The mixture was granulated and remaining 10 mg of (4)and 2.5 mg of (5) were added. The mixture was compression formed to givea tablet.

Experimental Example 1

Assay of Inhibitory Activity on Rat Steroid C_(17,20)-lyase

The activity was determined according to The Prostate, vol. 26, 140-150(1995).

Testes were excised from 13-week-old male SD rats, homogenized, andcentrifuged to give microsomes. [1,2-³H]-17-α-hydroxyprogesterone havinga final concentration of 10 nM, NADPH solution and test compounds weredissolved in 10 μl of 100 mM phosphate buffer (pH 7.4) and microsomeprotein (7 μg/10 μl) was added. The reaction mixture was incubated at37° C. for 7 minutes. Ethyl acetate (40 μl) was added and the mixturewas centrifuged. The substrate and the products (androstenedione andtestosterone) in the supernatant were separated by silica gel thin layerchromatography (TLC). The spots were detected and quantitativelydetermined by BAS 2000 Bioimage analyzer. The concentration of the testcompounds necessary to reduce the amount of the products by 50% (IC₅₀)relative to the amount of the products without test compound (control)as 100% was calculated, and shown in Table 1.

TABLE 1 Test IC₅₀ compounds (nM) Exam- ple 4

28 Exam- ple 6

15 Exam- ple 9

10 Exam- ple 13

8.3 Exam- ple 17

12 Exam- ple 27

11

Experimental Example 2

Assay of Inhibitory Activity on Testosterone Synthesis in Rats

Test compounds (50 mg/kg) were orally administered to 9-week-old male SD(Sprague Dawley) rats. Two hours after administration of the compounds,blood was drawn and testosterone concentration in the obtained serum wasmeasured by radioimmunoassay. The percentage (T/C, %) of thetestosterone concentration of test compounds administration group tothat of the control group was calculated, and taken as the inhibitoryactivity on testosterone synthesis.

TABLE 2 testosterone synthesis inhibitory activity Test compounds (T/C,%) Example 6

4.3 Example 9

4.6 Example 13

4.7

INDUSTRIAL APPLICABILITY

The compound of the present invention and a salt thereof have a steroidC_(17,20)-lyase inhibitory activity and are useful for the prophylaxisor treatment of various diseases such as primary tumor, its metastasisand recurrence thereof, various symptoms that accompany these cancers,prostatic hypertrophy, virilism, hirsutism, male pattern alopecia,precocious puberty, endometriosis, uterus myoma, mastopathy, polycysticovary syndrome and the like in mammal, which are affected by sexsteroids and metabolites thereof.

What is claimed is:
 1. A compound represented by the formula:

wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, or a salt thereof.
 2. The compound of claim 1,wherein R is (1) a hydrogen atom, (2) a formyl, (3) a C₁₋₆ alkylcarbonyloptionally substituted by 1 to 3 groups selected from Group 1, (4) aphenylcarbonyl optionally substituted by 1 to 3 groups selected fromGroup 1, (5) a C₁₋₆ alkyl-oxycarbonyl optionally substituted by 1 to 3groups selected from Group 1, (6) a phenyloxycarbonyl optionallysubstituted by 1 to 3 groups selected from Group 1, (7) a C₇₋₁₀aralkyloxy-carbonyl optionally substituted by 1 to 3 groups selectedfrom Group 1, (8) a trityl optionally substituted by 1 to 3 groupsselected from Group 1, (9) a phthaloyl optionally substituted by 1 to 3groups selected from Group 1 or (10) a N,N-dimethylaminomethyleneoptionally substituted by 1 to 3 groups selected from Group 1, R¹ is aC₁₋₆ alkyl or a C₃₋₆ cycloalkyl, R² is a C₆₋₁₀ aryl group optionallysubstituted by 1 to 4 groups selected from Group 2 or an aromaticheterocyclic group selected from Group 3, which is optionallysubstituted by 1 to 4 groups selected from Group 2, and R³ is (1) a C₁₋₄alkyl, (2) a C₁₋₄ alkyl having C₂₋₄ alkanoyl, carboxyl or C₁₋₄alkoxy-carbonyl as a substituent, (3) a hydroxyl group, (4) a C₁₋₄ loweralkoxy, (5) a C₁₋₄ alkanoyloxy, (6) a carbamoyloxy, (7) a carbamoyloxysubstituted by 1 or 2 C₁₋₄ alkyl groups, (8) a thiol group, (9) a C₁₋₄alkylthio group, (10) a C₁₋₄ alkanoylthio, (11) an amino group, (12) aC₁₋₄ alkylamino group, (13) a di-C₁₋₄ alkylamino, (14) a C₁₋₄alkanoylamino, (15) a formyl, (16) a C₂₋₆ alkanoyl, (17) a C₁₋₄alkylsulfonyl, (18) a carbamoyl group, (19) a mono- or di-C₁₋₁₀alkylcarbamoyl group, (20) a mono- or di-C₆₋₄ arylcarbamoyl, (21) amono- or di-C₇₋₁₆ aralkylcarbamoyl group, (22) a sulfamoyl, (23) a mono-or di-C₁₋₁₀ alkylsulfamoyl group, (24) a mono- or di-C₆₋₁₄ arylsulfamoylgroup, (25) a mono- or di-C₇₋₁₆ aralkylsulfamoyl group or (26) a halogenatom, and wherein, in the above, Group 1 comprises a substituentselected from the group consisting of: a halogen atom, a formyl group, aC₁₋₆ alkyl-carbonyl group and a nitro group, Group 2 comprises asubstituent selected from the group consisting of: (1) a C₁₋₆ alkylgroup, (2) a C₁₋₄ alkyl group substituted by 1 to 5 halogen atoms, (3) aC₁₋₄ alkyl group substituted by 1 or 2 C₁₋₄ alkoxy, (4) a hydroxylgroup, (5) a C₁₋₄ alkoxy group, (6) a C₁₋₄ alkanoyloxy group, (7) acarbamoyloxy group, (8) a carbamoyloxy group substituted by C₁₋₄ alkylgroup, (9) an amino group, (10) a mono- or di-C₁₋₄ alkylamino group,(11) a C₁₋₄ alkanoylamino group, (12) a formyl group, (13) a C₂₋₆alkanoyl group, (14) a C₁₋₄ alkylsulfonyl group, (15) a carbamoyl group,(16) a mono- or di-C₁₋₁₀ alkylcarbamqyl group, (17) a C₃₋₆cycloalkylcarbamoyl group, (18) a mono- or di-C₆₋₁₄ arylcarbamoyl group,(19) a mono- or di-C₇₋₁₆ aralkylcarbamoyl group, (20) a sulfamoyl group,(21) a mono- or di-C₁₋₁₀ alkylsulfamoyl group, (22) a mono- or di-C₆₋₁₄arylsulfamoyl group, (23) a mono- or di-C₇₋₁₆ aralkylsulfamoyl group,(24) a halogen atom, (25) a cyano group and 26) an oxo group, and Group3 comprises a substituent selected from the group consisting of: a2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridylgroup, a 4-pyridyl group, a 2-turyl group, a 3-furyl group, a 2-quinolylgroup, a 4-quinolyl group, a 8-quinolyl group, a 3-isoquinolyl group, a4-isoquinolyl group, a pyrazinyl group, a 2-pyrimidinyl group, a3-pyrrolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a1-pyrazolyl group, a 2-thiazolyl group, a 4-thiazolyl group, a5-thiazolyl group, a 3-isothiazolyl group, a 4-isothiazolyl group, a2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, a 3-isoxazolylgroup, a 3-pyridazinyl group, a 1-indolyl group, a 1-isoindolyl group, a2-isoindolyl group, a 1-tetrazolyl group, a 2-tetrazolyl group and a5-tetrazolyl group.
 3. The compound of claim 1, wherein R is a hydrogenatom, R¹ is a C₁₋₆ alkyl group or a C₃₋₆ cycloalkyl group, R² is aphenyl group, a pyridyl group, a thienyl group, a furyl group or anizoindolinyl group, each optionally substituted by 1 to 4 groupsselected from Group 4, n is 0 or 1, and R³ is a C₁₋₄ lower alkoxy group,a C₁₋₄ alkanoyloxy group or a C₁₋₄ alkanoylamino group, and wherein, inthe above, Group 4 comprises a substituent selected from the groupconsisting of: (1) a C₁₋₆ alkyl group, (2) a C₁₋₄ alkyl groupsubstituted by 1 to 5 halogen atoms, (3) a C₁₋₄ alkyl group substitutedby 1 or 2 C₁₋₄ alkoxy, (4) a C₁₋₄ alkoxy group, (5) a C₁₋₄ alkanoylaminogroup, (6) a C₂₋₆ alkanoyl group, (7) a mono- or di-C₁₋₁₀ alkylcarbamoylgroup, (8) a C₃₋₆ cycloalkylcarbamoyl group, (9) a mono- or di-C₁₋₁₀alkylsulfamoyl group, (10) a halogen atom, (11) a cyano group and (12)an oxo group.
 4. The compound of claim 3, wherein R² is a phenyl group,a pyridyl group, a thienyl group, a furyl group or an isoindolinylgroup, each optionally substituted by 1 or 2 groups selected from Group5, and wherein, in the above, Group 5 comprises a substituent selectedfrom the group consisting of: (1) a C₁₋₄ alkanoylamino group, (2) a C₂₋₆alkanoyl group, (3) a mono-C₁₋₁₀ alkylcarbamoyl group, (4) a mono-C₁₋₁₀alkylgulfamoyl group, (5) a halogen atom and (6) an oxo group.
 5. Thecompound of claim 1, wherein R is a hydrogen atom, R¹ is a C₁₋₆ alkylgroup, R² is (1) a phenyl group substituted by halogen or acetylamino or(2) a pyridyl group substituted by halogen or acetylamino, and n is 0.6. The compound of claim 1, which is1-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-(1H-imidazol-4-yl)-2-methyl-1-propanol,(−)-N-(6-{4-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]phenyl}-2-pyridyl)acetamide,(−)-N-{4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl][1,1′-biphenyl]-3-yl}acetamide,4′-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl[1,1′-biphenyl]-3-carboxamideorN-[4′-[1-hydroxy-1-(1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl]acetamide,or a salt thereof.
 7. A prodrug of a compound represented by theformula:

wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, or a salt thereof.
 8. A pharmaceutical compositioncomprising a compound represented by the formula:

wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents. athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, a salt thereof or a prodrug thereof.
 9. A method fortreating a tumor in a mammal in need thereof, said method comprisingadministering a composition of claim 8, to a mammal in need thereof. 10.The method of claim 9, wherein said tumor is breast cancer or prostatecancer.
 11. An androgen reducer composition Comprising a compoundrepresented by the formula;

wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, or a salt thereof or a prodrug thereof, and an LHRHmodulator in combination.
 12. A production method of a compoundrepresented by the formula:

wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, or a salt thereof, which method comprises reacting acompound represented by the formula:

wherein each symbol is as defined above, with a reaction product of acompound represented by the formula:

wherein X is a leaving group and R is as defined above, and a Grignardreagent or alkyllithium.
 13. A method for inhibiting steroidC_(17,20)-lyase, which comprises administering, to a mammal, aneffective amount of a compound represented by the formula:

wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, and n is aninteger of 0 to 4, or a salt or a prodrug thereof.
 14. A method formaking a pharmaceutical composition useful as a steroid C_(17,20)-lyaseinhibitor comprising combining a compound represented by the formula:

wherein R is a hydrogen atom or a protecting group, R¹ is a lower alkylgroup or a cyclic hydrocarbon group, R² is an aromatic hydrocarbon groupoptionally having substituents or an aromatic heterocyclic groupoptionally having substituents, R³ is a hydrocarbon group optionallyhaving substituents, a hydroxyl group optionally having substituents, athiol group optionally having substituents, an amino group optionallyhaving substituents, an acyl group or a halogen atom, n is an integer of0 to 4, or a salt thereof or a prodrug thereof with a pharmaceuticallyacceptable carrier, excipient or diluent.